Noninvasive measurements in a human body

ABSTRACT

Apparatus and methods are provided including directing acoustic radiation toward a region of interest within a subject&#39;s body. Light is transmitted from a light emitter to a light detector such that a first light portion is transmitted without passing through the subject&#39;s tissue, and a second light portion is transmitted via the region of interest. Scattered light of the second light portion contains a tagged component corresponding to photons tagged by the acoustic radiation, and an untagged component corresponding to photons untagged by the acoustic radiation. Light of the first light portion undergoes an interaction with light of the second light portion at the light detector. A property of tissue of the region of interest is determined, by decoupling from each other the tagged and untagged components of the second light portion, based upon the interaction between the light of the first and second light portions.

FIELD OF THE INVENTION

This invention is generally in the field of medical devices, and relatesto a method and system for noninvasive measurements in a human body. Theinvention is particularly useful for monitoring such parameters of thehuman body as oxygen saturation and/or concentration of analyte(s) inblood.

BACKGROUND OF THE INVENTION

Monitoring of the oxygenation level of a tissue region is required inorder to determine if the tissue is viable or necrotic. For example,measuring the oxygen saturation level allows for determining whether apatient that experienced a stroke event should undergo a therapeuticprocedure, whether a certain procedure is not necessary or whetherperforming certain procedures entails a high risk. Such measurements arealso imperative for determining the efficiency of a treatment.

Near infrared light has been used to non-invasively probe the patient'sbrain based on different absorption characteristics of oxygenated anddeoxygenated hemoglobin. However, near infrared spectroscopy (NIRS)suffers from several drawbacks associated for example with the fact thatdifferential scattering of two different wavelengths used in themeasurements result in an uncertainty in the path length that eachwavelength passes; an inherent inability to localize the probed volumewhich requires computation-intensive tomographic devices and algorithmsto resolve; analysis of the detected signal depends on a model beingused to characterize the tissue structure being probed. This impedes theuse of NIRS in real time medical settings.

U.S. Pat. No. 5,293,873 discloses a measuring arrangement fortissue-optical examination of a subject with visible, NIR or IR light.According to this technique, coherent light and ultrasound are directedat the subject along parallel propagation paths. The ultrasound causes aDoppler shift in the light emerging from the subject, this shift beingrelated to certain tissue characteristics. The light emerging from thesubject is detected and a corresponding signal is supplied to anevaluation stage which absolutely or relatively calculates the intensityof those parts of the detected light which proceeded through tissue notcharged by ultrasound and those parts of the detected light whichproceeded through tissue charged by ultrasound.

SUMMARY OF THE INVENTION

There is a need in the art to facilitate noninvasive measurements in ahuman body, by providing a novel method and system capable of monitoringblood or other fluid medium and/or tissue parameters in a human body,for example the concentration of an analyte in blood, fluid reservoirsor tissue regions. The technique of the present invention is capable ofquantitatively monitoring cerebral oxygenation or blood volume so as toprovide for example continuous information about the status of cerebraltissues for patients with a risk of neurological injuries.

The present invention utilizes the principles of ultrasound tagging oflight. According to the present invention, tagging of light withacoustic radiation is used to enable distinguishing between the opticalresponse of a region of interest (e.g., cerebral tissue, blood vessel)and regions outside the region of interest; and/or to significantlyimprove oximetry and pulse oximetry based measurements.

Thus, a body part is illuminated with at least one wavelength of light,and is irradiated with acoustic radiation (preferably ultrasound) suchthat the acoustic radiation overlaps with the illuminated region in thebody (this overlapping volume is termed “tagged volume”). Lightscattered from the body is appropriately detected. This scattered lightincludes photons tagged and untagged by the acoustic radiation.

According to the invention, an acoustic unit is operated with at leasttwo different operating conditions, to thereby irradiate a certainregion of a body part (region of interest) with acoustic radiation withat least one varying characteristic of said acoustic radiation. Forexample, the at least one variable characteristic is selected so as toprovide at least two different effective optical pathlengths of thetagged photons scattered at the region of interest. A relation betweenmeasured data corresponding to the different conditions of the acousticradiation (e.g., resulting in the different effective opticalpathlengths) is indicative of a property of a tissue component in theregion of interest.

The at least two different operating conditions of the acoustic unit (atleast two different values of an acoustic radiation characteristic) maybe selected so as to irradiate different volumes of the region ofinterest (i.e., the different tagged volumes substantially overlap inspace), and/or to provide different tagging efficiencies. Theirradiation of different volumes can be achieved by generating pulses ofacoustic radiation having different duration and/or generating acousticradiation of different beam waists. The different tagging efficienciescan be obtained by generating pulses of acoustic radiation havingdifferent amplitude and/or frequency and/or gradient of chirping.

It should be noted that the term “property of a tissue” used hereinsignifies at least one parameter of a medium or media in a region ofinterest, where the media may include fluid or any other tissue.

The term “effective optical pathlength” signifies an optical pathlengthfrom an illumination assembly (its light output port) to a detectionassembly (its light input port) which accounts for tissue scattering.

The term “tagging efficiency” signifies a number of tagged photonsrelative to a number of untagged photons scattered by scattering centersinside a tagged volume.

The term “different volumes” or “different tagged volumes” refers tovolumes substantially within the same location relative to the acoustictransducer arrangement, namely volumes that substantially overlap inspace, such that the average optical and acoustic characteristics of thetagged volumes are about the same during and in between the differentmeasurements; therefore the relative change in the tagged volume betweenthe two measurements is smaller than the tagged volume.

Preferably, a body part (e.g., a human head) containing a region ofinterest (e.g., cerebral tissue) is illuminated with light (e.g., of atleast two different wavelengths) and is irradiated with acousticradiation, in a manner to ensure optimal operating condition formeasurements. This optimal operating condition is such that theilluminating light and acoustic radiation overlap within the region ofinterest and thus light scattered from the region of interest is“tagged” by acoustic radiation (the light is modulated by the frequencyof the acoustic radiation) while substantially do not overlap in aregion outside the region of interest. Moreover, the optimal operatingcondition is such as to ensure that detected light includes a portion oflight scattered by the region of interest and tagged by acousticradiation, and a portion of untagged light scattered by regions outsidethe region of interest. This allows for distinguishing between the lightresponses of the region of interest and its surroundings (e.g., cerebraland extracranial tissues; a vascular cavity and surrounding tissues; ora blood pool and surrounding tissues).

It should be understood that acoustic radiation may be in the form ofcontinuous waves, or pulses- or bursts-based acoustic radiation.

The technique of the present invention can be used in pulse oximetrymeasurements for determining oxygen saturation level in a region ofinterest. Comparing the technique of the present invention to pure pulseoximetry measurements that are highly sensitive to minor movements of abody, measured data obtained by the technique of the present invention,being for example in the form of a power spectrum of a tagged lightresponse of the region of interest, is practically insensitive tomovements of regions outside the region of interest.

Preferably, measured data is in the form of time dependent and/orwavelength dependent variations of the tagged light signals for at leasttwo wavelengths of illuminating light.

The present invention provides for non-invasively determining suchparameters as oxygen saturation level in the region of interest,concentration of a substance (e.g. blood, hemoglobin) or a structurewithin the region of interest, the presence and concentration oflamellar bodies in amniotic fluid for determining the level of lungmaturity of the fetus, the presence and/or concentration of meconium inthe amniotic fluid, presence and/or concentration of blood in theamniotic fluid; as well as for noninvasive monitoring the opticalproperties of other extravascular fluids such as pleural, pericardial,peritoneal (around the abdominal and pelvis cavities) and synovialfluids.

According to the invention, acoustic (ultrasound) radiation used formeasurements may or may not be focused, since the measurements utilizeultrasound tagging for the purposes of distinguishing between lightresponses of the region of interest and its surroundings and/or forincreasing signal to noise ratio of ultrasound tagging basedmeasurements, while not necessarily for imaging. The invention may alsobe used for imaging of a body part, namely, for mapping the opticalattenuation of the body tissues. This is implemented by appropriatelyoperating optical and acoustic units.

The present invention may utilize the principles of oximetry forprocessing the measured data. To this end, the illumination with atleast two different wavelengths is applied. In some embodiments, thelight response signals are collected over a time period larger than aheart beat, and the principles of pulse oximetry are used to determinethe oxygen saturation level.

The present invention may be used to measure the concentration of asubstance in a body region using illumination with at least a singlewavelength. In some embodiments, the wavelength is selected tocorrespond to a characteristic wavelength being selectively absorbed orscattered by the substance. For example, the redox state of cytochrome-coxidase can be monitored at a wavelength (or a selection of wavelengths)being indicative of oxygen availability and metabolic activity of thetissue. As another example, potassium depolarization is affected byhypoxia. Thus, measurement of potassium related optical changes is anindirect indicator of changes in oxygenation. Contrast agents, such asindocyanine green (ICG) can also be monitored using the technique of thepresent invention, where the contrast agent is administered throughblood vessels that perfuse the region of interest, both the dynamics ofchanges in the concentration of the contrast agent and the absoluteconcentration can be determined. Other tissue analytes such asbilirubin, glucose and urea, can be monitored using appropriateselection of wavelengths for illumination.

Preferably, a measurement unit (an illumination assembly, a lightdetection assembly, and an acoustic transducer arrangement) is placed inclose contact with the respective body portion (e.g., the skinoverlaying the skull). As indicated above, the illumination assembly isconfigured and operable to illuminate the body portion with at least twowavelengths. The acoustic transducer arrangement is configured andoperable to transmit acoustic radiation into the same volume from whichthe light detector collects scattered light.

The light detection assembly may be oriented for collecting both backscattered light and forward scattered light.

The present invention preferably utilizes imaging of a region ofinterest prior to or concurrently with applying measurements thereto.This is in order to assist in determining an optimal positioning of ameasurement system (its probe device) to provide the optimized operatingcondition for measurements. The imaging may be implemented usingultrasound, magnetic resonance (MR), computed tomography (CT) orpositron emission tomography (PET). If ultrasound-based imaging is used,it can be implemented either using or not the same ultrasound transducerarrangement that is used for measurements.

Preferably, the invention also provides for using ultrasound radiationfor determining such parameters of blood in the region of interest asblood flow, tissue velocity profile, etc. To this end, reflections ofultrasound radiation from the irradiated region are analyzed using anyknown suitable Doppler-based techniques. The incident ultrasoundradiation may be in the form of continuous waves or pulses (gates).

There is thus provided according to one broad aspect of the presentinvention, a measurement system for use in non-invasive measurements ona human body, the system comprising:

a measurement unit comprising an optical unit having an illuminationassembly and a light detection assembly; and an acoustic unit forgenerating acoustic radiation; the measurement unit being configured andoperable to provide an operating condition such that the acousticradiation overlap with a certain illuminated region in the body, andthat the detection assembly collects light scattered from said certainregion, measured data generated by the detection assembly being therebyindicative of scattered light having photons tagged and untagged by theacoustic radiation, thereby enabling to identify a light response ofsaid certain region to illuminating light;

-   -   a control unit connectable to the optical unit and to the        acoustic unit, the control unit being preprogrammed to operate        the acoustic unit with at least two different operating        conditions to vary at least one characteristic of acoustic        radiation, the control unit being responsive to the measured        data and preprogrammed to process and analyze the measured data        to extract therefrom a data portion associated with the light        response of said certain region, thereby enabling determination        of a property of a tissue component in said certain region based        on a relation between the measured data corresponding to the at        least two different operating conditions of the acoustic unit.

According to another broad aspect of the invention, there is provided amethod for use for non-invasive measurements in a human body, the methodcomprising: applying acoustic radiation to a certain illuminated regionin the body, with at least two different conditions of the appliedradiation achievable by varying at least one characteristic of theacoustic radiation; detecting light scattered from the body part andgenerating measured data indicative of detected photons tagged anduntagged by the acoustic radiation; analyzing the measured data toextract therefrom a data portion corresponding to the tagged photons andbeing therefore associated with a light response of said certain region,to thereby enable determination of tissue properties of said certainregion based on a relation between the measured data portionscorresponding to the at least two different operating conditions.

According to yet another broad aspect of the invention, there isprovided a probe device for use in a system for monitoring tissueproperties in a human body, the probe comprising: a support structureconfigured to contact a body portion, said support structure carrying anarray of at least two light output ports arranged in a spaced-apartrelationship and being connectable to a light source assembly, an arrayof light input ports arranged in a spaced-apart relationship and beingconnectable to a light detection assembly, and at least one acousticoutput port of an acoustic unit, the arrangement of the light ports andthe acoustic port being such as to allow selection of at least one ofsaid light output ports, at least one of the light input ports and atleast one of the acoustic output ports such that acoustic radiation of apredetermined frequency range coming from said at least one selectedacoustic output port and illuminating light coming from said at leastone selected light output port overlap within a region of interest inthe body, and in that said at least one light input port collects lightscattered from the overlapping region and light scattered from outsidethe region of interest.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the invention and to see how it may be carriedout in practice, preferred embodiment will now be described, by way ofnon-limiting examples only, with reference to the accompanying drawings,in which:

FIGS. 1A to 1C schematically illustrate three different examples,respectively, of a monitoring system according to the invention formonitoring a region of interest in a human or animal body;

FIG. 1D is a flow diagram of a method of the present invention;

FIG. 1E is a flow diagram of an example of a measurement technique ofthe present invention;

FIGS. 2A and 2B schematically illustrate the principles of a measurementscheme according to an example of the invention;

FIG. 2C exemplifies another possible example of affecting an effectiveoptical pathlength of tagged photons scattered from a region ofinterest;

FIG. 3 is a flow diagram of an example of a method of the inventionutilizing the measurement scheme of FIGS. 2A and 2B;

FIGS. 4A and 4B schematically illustrate two examples of the monitoringsystem configuration suitable for monitoring the oxygen saturation inthe internal jugular vein of a human;

FIGS. 5A and 5B schematically illustrate two examples of configurationof a measurement unit suitable to be used in the system of the presentinvention to carry out detection of required parameter(s) of a region ofinterest using a local oscillator method;

FIGS. 6A and 6B schematically illustrate two examples of configurationof a measurement unit suitable to be used in the system of the inventionutilizing a phased array acoustic transducer arrangement;

FIGS. 7A-7B and 8A-8B exemplify various configurations of a supportstructure (probe) of the present invention carrying at least part of ameasurement unit.

DETAILED DESCRIPTION OF THE INVENTION

Reference is made to FIGS. 1A-1C illustrating schematically threespecific but not limiting examples of a measurement system, generallydesignated 100, configured and operable according to the invention fornon-invasive measurements of one or more parameters (properties oftissue components) of a region of interest 200 in a human or animalbody. This may be an oxygen saturation level, or various otherparameters such as the concentration of an analyte in the patient'sblood, or the perfusion of an analyte/metabolite in tissues. Tofacilitate understanding, the same reference numbers are used foridentifying components that are common in all the examples of theinvention.

The system 100 includes a measurement unit 101 and a control unit 120.The measurement unit 101 includes: an optical unit 101C formed by anillumination assembly 101A and a light detection assembly 102A; and anacoustic unit formed by a transducer arrangement 110. The control unit120 is configured to control the operation of the measurement unit 101and to process and analyze measured data generated by the measurementunit 101.

The illumination assembly 101A may include one or more illuminator unitsassociated with one or more locations, respectively, with respect to theregion of interest. Similarly, the detection assembly 102A may includeone or more detector units associated with one or more detectinglocations, respectively. The illuminator unit may include one or morelighting elements; as well as the detector unit may include one or morelight detecting elements. The lighting element is formed by a lightemitter and possibly also a light guiding unit (e.g., an optical fiberor fiber bundle); the light detecting element is formed by a lightsensor and possibly also a light guiding unit (e.g., optical fiber orfiber bundle).

In the example of FIG. 1A, the illumination assembly 101A includes asingle illuminator unit, and the light detection assembly 102A includesa single detector unit. This does not necessarily signify a singleilluminating element and/or a single detecting element, but may refer toan array of illuminating element provided they are associated with thesame location with respect to the region of interest, and/or an array ofdetecting element associated with the same location relative to theregion of interest.

The optical unit 101C and the acoustic unit 110 are connectable to thecontrol unit 120 via wires or wireless means. The control unit 120 istypically a computer system including inter alia a power supply unit(not shown); a control panel with input/output functions, a datapresentation utility (display) 120A; a memory utility 120B; and a dataprocessing and analyzing utility (e.g. CPU) 120C. Also provided in thecontrol unit 120 are a signal generator (e.g. function generator andphase control) 122 configured and operable to control the operation ofthe transducer arrangement 110, and an appropriate utility 123configured for operating the optical unit 101C. The CPU 120C ispreprogrammed for receiving measured data MD coming from the detectionassembly 102A and for processing this data to determine desiredparameter(s) of the region of interest, e.g., oxygen saturation level.

In the present examples, the measurement unit 101 is configured as aprobe having a support structure (preferably flexible) 403 to be put onthe body part to be measured. The support structure 403 carries at leastpart of the illumination assembly 101A (at least one light outputport—single output port OP in the example of FIG. 1A and multiple portsin examples of FIGS. 1B-1C) and at least part of the detection assembly102A (at least one light input port—single input port IP in the exampleof FIG. 1A and multiple ports in examples of FIGS. 1B-1C).

It should be understood that the light output port OP may be integralwith the light emitting element(s) or may be constituted by a distal endof an optical fiber unit connected at its other end to light emittingelement(s) located outside the support structure (e.g., at the controlunit). Similarly, the light input port IP may be integral with the lightdetecting element(s) or may be constituted by a distal end of an opticalfiber unit which by its other end is connected to light detectingelement(s) located outside the support structure (e.g., at the controlunit).

Generally, the illumination assembly 101A can be configured to producelight of a single wavelength. Preferably, the illumination assembly 101Ais configured for generating light of at least two differentwavelengths. To this end, the illumination assembly may include at leasttwo light emitters (e.g., laser diodes), for example one emitting narrowbandwidth photons of a wavelength within the range of 605 nm to 805 nmand the other emitting photons of a wavelength within the range of 800nm to 1300 nm; or may include a broadband light source. The illuminationassembly 101A may for example be preprogrammed to produce the differentwavelength components at different times, or simultaneously producewavelength components with different frequency- and/or phase-modulation.Accordingly, the control unit 120 is preprogrammed to identify, in asignal generated by the detection assembly 102A, the correspondingwavelength of the irradiating light, using time, and/or phase and/orfrequency analysis. The detection assembly may include an appropriatefrequency filter.

Thus, the illumination assembly 101A may include light emitter(s)carried by the support structure 403 and communicating with the controlunit 120 using wires 106 or wireless signal transmission. Alternatively,the light emitter(s) may be located outside the support structure 403(e.g., within the control unit 120) and connector 106 is constituted bya light guiding assembly (e.g., optical fibers) for guiding light to thelight output port OP located on the support structure 403.

The detection assembly 102A includes one or more light detectors. Thismay be a photomultiplier tube, photodiode, avalanche photodiode, orpreferably an image pixel array, e.g., CCD or an array of photodiodes.The detector(s) may be accommodated outside the support structure(probe) 403, e.g., may be located within the control unit 120, andreturned light (light response) may be guided from the input port IP ofthe detection assembly via light guiding means 105 (e.g., opticalfibers). Alternatively, the detector(s) may be located at the supportstructure and connector 105 is configured to connect an electricaloutput of the detector(s) indicative of measured data MD to the controlunit 120.

It should also be understood that connectors 105 and 106 may be electricwires connecting the control unit 120 to the illumination assembly anddetection assembly located on the probe 403, or the connection may bewireless.

Thus, generally, the terms “illumination assembly” and “detectionassembly” as carried by a support structure which is brought in contactwith a body part to be measured, are constituted by at least lighttransmitting and receiving ports.

It should be noted that, for the purposes of the present invention, thelight input port of the detection assembly 102A can be larger than thatused for imaging by means of diffuse light. In diffuse light imaging,localization is achieved by small input ports; otherwise light from alarge volume is collected. According to the invention, light collectionfrom a large volume is desired, since localization is achieved by theultrasound tagging. Hence, the input port of the detection assembly 102Ais optimized to collect light from a substantially large volume oftissue and/or blood, for example by using large area detectors or CCDcameras or an array of detectors comprising a single input port.

As indicated above, the detection assembly 102A may include two separatedetectors or an array of detectors. Each detector may be coupled to abandpass filter configured for transmitting light of a corresponding oneof the wavelengths produced by the illumination assembly 101A. Thebandpass filters may include high-pass, low-pass and bandpass opticalfilters. Alternatively narrow bandwidth detectors can be used.

The transducer arrangement 110 may be located on the support structure403 and connected to the control unit 120 (its signal generator 122 andCPU 120C) using cables and/or optical fibers 107 and/or using wirelessmeans. Alternatively, connector 107 may constitute an acoustic guidingunit for connecting the transducer(s) located outside the supportsstructure (e.g., at the control unit 120) to an acoustic output port 245on the support structure.

In the case actual light detectors are placed on the flexible supportstructure (probe) 403, the detectors are preferably mechanically andelectronically isolated such that acoustic waves propagating from theacoustic output port 245 minimally affect the collection of photons bythe detectors and the transduction of light signals into electronicsignals. If the ultrasound transducer arrangement 110 is also placed onthe probe 403, then the configuration is such as to prevent RF and otherelectronic signals generated by the transducer arrangement frominterfering with the collection of photons by the detectors and with thetransduction of light signals into electronic signals. This isimplemented using a shielding arrangement, for example includingelectrical isolation of the detectors by appropriate materials that arepoor conductors, or by creating a Faraday cage around the detectors(detecting elements), or creating mechanical isolation by usingappropriate materials that attenuate the propagation of sheer acousticwaves through the probe itself or through the body tissues. As indicatedabove, detectors may be connected to the probe 403 using connectingports (possibly detachable). The connecting ports are configured toisolate mechanical and electrical signals at the frequencies generatedby the ultrasound transducer arrangement and at other frequencies.

The transducer arrangement 110 may be a single acoustic element,configured and operable for emitting focused or unfocused acoustic beamsor emitting acoustic pulses; or a piezoelectric phased array capable ofproducing acoustic beams with variable direction, focus, duration andphase; or may be an array of silicon units or other pressure generatingunits configured as a single element or an array of elements (phasedarray); or a complete ultrasound imaging probe comprising transmittingand receiving units. The transducer arrangement may be connected to anamplifier (not shown) located within the control unit 120 and operableto amplify electronic signals generated by the signal generator 122. Thecontrol unit is preprogrammed to operate the transducer arrangement 110(via the signal generator 122) in a predetermined manner as will bedescribed below.

In addition, the transducer arrangement 110 may include an array oflaser generated ultrasound elements (LGU) coupled to a laser sourcecapable of emitting short pulses of light (e.g., of the order of 10nsec-100 μsec). These short pulses of light are transmitted to thetransducer arrangement 110 via optical fibers to produce acoustic wavesat a desired frequency, time and duration. The onset of light pulsesemitted in each element may experience a relative time delay between theelements. This delay creates a phase delay between the generatedacoustic waves at each element and can be used to focus or stir thegenerated beams towards a desired location (i.e. the region of interest200). Elements for laser generated ultrasound transducers are known inthe art, for example such as disclosed in PCT application WO03057061.Using such a transducer arrangement will make the probe 403 cheaper,since the elements of the probe are optical fibers. When LGU elementsare used, the control unit 120 controls the activation of laser sourcesemitting short pulses to create acoustic waves, in accordance with anembodiment of the present invention, referring to the activation of thesignal generator. For example, the control unit 120 may activate thelasers such that they emit a series of short pulses consecutively inorder to create a specific duration of acoustic bursts; or control unit120 may control the amplitude of the laser pulses, such that theamplitude of the acoustic waves generated by the LGU elements isdetermined according to a specific embodiment of the invention as willbe described below.

The detection assembly 102A generates electronic signals in response tothe amplitude and phase of photons reaching the input port IP. Theseelectronic signals may be filtered by analog or digital filters, forexample bandpass filters, that are appropriately provided beingconnected to the data processing utility 120C of the control unit 120 orbeing a part of this processing utility. The bandwidth of these filterscan be fixed or changed by the control unit 120. The bandwidth tuningcan be performed optically by heterodyne detection or by using aplurality of filters having different bandwidths, or by tunable filterswhich are coupled to each detector. Alternatively, filters can beelectronic. Preferably, prior to performing the actual measurements, anoptimal positioning of the assemblies of the optical unit and of theacoustic unit with respect to region of interest 200 is provided tosatisfy an operating condition for measurements. The operating conditionis such that both the illuminating light 250 (at least a portionthereof) and the acoustic radiation 255 irradiate the same region(volume) simultaneously, while substantially not overlapping in outsideregions; and that the detection assembly detects light scattered fromthe region of interest 200 and regions outside thereof. Generallyspeaking, the positioning of the optical unit and transducer arrangementwith respect to the region of interest 200 is such as to enable todistinguish between scattered photons collected from region 200 andregions 11 outside this region, using acoustic tagging of light. As willbe described further below, the region of interest may be identified bythe control unit 120.

As indicated above, the pre-positioning may be carried out using anultrasound imaging. An imaging system of any known suitableconfiguration may be used, which may utilize the same transducerarrangement 110 used for the measurement process or another ultrasoundtransducer(s). Ultrasound images of a body part containing the region ofinterest 200 are acquired and analyzed by the control unit 120 (which inthis case is installed with a suitable image processing utility) oranother appropriately preprogrammed computer system, to determine theoptimal positioning of the optical unit 101 (namely the illuminationassembly 101A and the detection assembly 102A) relative to the region ofinterest and relative to the acoustic unit 110.

The illumination assembly 101A is preferably placed at the shortestdistance to the region of interest 200. Preferably, the illuminationassembly 101A is placed such that a light path between the illuminationassembly 101A and the region 200 is that suffering the least attenuationat the wavelengths chosen for measurements, as compared to the otherpaths. A distance between the illumination assembly 101A and thedetection unit 101B is preferably determined to be at least equal to andpreferably larger than a distance between the illumination assembly 101Aand region 200.

Preferably, the support structure 403 is configured to define variouspositions for attaching the detection assembly 102A and/or theillumination assembly 101A to be at the correct distance between them.For example, these positions may be determined by using a sliding bar(not shown) that is attached to the light detection assembly 102A andcan be secured to the support structure 403 using a small screw or alatch. Alternatively, a plurality of light output ports and/or pluralityof light input ports are provided on the support structure 403 and thecontrol unit 120 operates to select the appropriate light source(s) anddetector(s) (light output port and light input port) for measurements.This selection is based on the signals generated by each detector and onthe geometry of the body part and the position of the region of interesttherein.

Additionally, the illumination assembly 101A and the detection assembly102A are placed such that the light output port OP of the illuminationassembly and the light input port IP of the detection assembly are inclose contact with an outer skin 10 of the body part. Optionally, anindex matching oil or adhesive is used to reduce reflection of lightfrom the outer skin 10. The adhesive may be used to secure the supportstructure 403 to a specific location on the body part. Alternatively, oradditionally, a belt can be used to prevent movement of the supportstructure 403.

Once the position of the illumination and detection assemblies is fixed,the acoustic transducer arrangement 110 is positioned such that acousticwaves 255 generated by the transducer arrangement 110 are coupled intothe appropriate body part, propagate therethrough and reach the regionof interest 200. For example, in the case the illumination and detectionassemblies are appropriately placed to illuminate and collect lightscattered by region 200, the transducer arrangement 110 is placed suchthat acoustic waves 255 propagate through the same part of region 200from which scattered photons 250 are detected by the detection assembly102A. The transducer arrangement 110 may be fixed to an appropriatelocation using an ultrasound transmitting adhesive or acoustic couplingmaterial (such as gel or a hydrogel adhesive, or ultrasound compatibleglue), and optionally a belt for fixing the transducer to one location.The ultrasound transducer arrangement 110 may be configured as a phasedarray transducer producing a focused beam that is being scanned over aregion of skin 10 overlaying the body part.

Having optimally positioned the illumination and detection assembliesand the acoustic transducer arrangement, measurements are taken byappropriately operating the measuring unit 101. The control unit 120actuates the illumination assembly 101A to generate photons 250(preferably of at least two different wavelengths). The illuminationassembly 101A may be configured and operable to produce a continuousstream of photons 250 (CW), or a time modulated stream (at a certainfrequency W), or a train of pulses. Photons 250 propagate through thebody part and reach region 200. A portion of photons 250 is absorbed byregion 200 and a portion of photons 250 is scattered by this region 200and by its surroundings 11. A portion of the scattered photons 250propagates through the body part (surroundings of the region ofinterest) and reaches the detection assembly 102A. The latter collectsat least a part of these photons and generates measured data MDindicative thereof, i.e., an electric signal in response to the numberof photons that are collected at the input port IP of the detectionassembly at a specific point in time for each irradiating wavelengthgenerated by the illumination assembly 101A.

It should be noted that, in the case the detection assembly 102A isspaced from the illumination assembly 101A a distance equal to or largerthan twice the minimal distance between the region 200 and theillumination assembly 101A, the detection assembly 102A collects bothback and forward scattered photons. In the case the illuminationassembly 101A includes a laser with a coherence length larger than theoptical path of scattered photons in the tissue, an interference patternresulting in a speckle image is generated on the input port IP of thedetection assembly. In order to detect and analyze the speckle image,the detection assembly 102A may include an array of detectors with anindividual size comparable to that of individual speckle.

FIG. 1D illustrates a flow diagram of the main steps in a method of thepresent invention for measurement in a human body. The optical andacoustic units are appropriately applied to the body. The optical unitis operated (by the control unit) to illuminate the body with at leastone wavelength. As photons 250 illuminate region 200, the transducerarrangement 110 is operated with at least two different operatingconditions defined by varying at least one characteristic of acousticradiation 255. Acoustic radiation propagates through the body toirradiate a volume of region 200 from which scattered photons 250 aredetected by the detection assembly 102A. The tagged volume correspondsto this acoustically irradiated volume at the measurement time. Theinteraction of acoustic waves 255 with photons 250 results in that thefrequency of photons 250 is shifted by the frequency of acoustic waves255. In addition, photons 250 scattered within the tagged volumeexperience a modulation of the optical pathlength resulting frommodulation of the density of scattering centers and from their acousticinduced motion. Acoustic radiation operated with at least two differentconditions irradiates the tagged volume. The two conditions correspondto two different effective optical pathlength of tagged photonsscattered within the tagged volume. The effective optical pathlengthsdepends on the volume of the tagged volume and/or on changes in thetagging efficiency of photons scattered within the tagged volume. Thedetection assembly 102A detects the modulated photons (“tagged photons”)and the unmodulated photons at the original frequency (“untaggedphotons”) at the two measurement conditions, for each of theilluminating wavelengths. The detection assembly 102A generates measureddata MD (electric signals) indicative of the detected photons. Themeasured data portion corresponding to the tagged photons is termed“tagged signal”.

The control unit 120 processes the measured data MD to determine arelation between data portions corresponding to the different taggedphotons, i.e., tagged photons having different effective pathlengths asa result of different characteristics of the acoustic radiation. Thisrelation between the data portions is indicative of a difference inoptical attenuation, and is therefore indicative of a tissue propertywithin the illuminated and acoustically irradiated body region. Examplesof the acoustics unit operation providing the different characteristicsof the acoustic radiation will be described further below with referenceto FIGS. 2A-2C.

The data processing includes an appropriate algorithm according to thetype of detection used. For example, in the case of a single (largearea) detector, a known heterodyne detection technique (e.g., describedin Lev A. and B. G. Sfez Optics Letters (2002) 27 (7) 473-475) is usedto extract, from the measured data, a data portion indicative of thesignal of the tagged photons. When a CCD camera is used and a fullspeckle image is detected, another known suitable technique for exampledescribed by Leveque-Fort et al. in Optics Communication 196 127-131(2001) can be used to determine the optical signal of photons scatteredfrom the particular volume which is tagged by acoustic waves. Otherpossible algorithms are described below.

As indicated above, more than one light input port IP as well more thanone light output port OP may be provided in the measurement system 100.This is exemplified in FIG. 1B. Here, a measurement system 100 utilizesa pair of light input ports IP₁ and IP₂ and a pair of light output portsOP₁ and OP₂. It should be understood that more that two input/outputports can be used. In addition, each port may serve as a dual lightinput and output port, by using a fiber combiner/splitter that coupleslight into and out of one optical fiber. The ports may be arranged in aone-dimensional array or a two-dimensional array to improve flexibilityof use.

FIG. 1C exemplifies a measurement system 100 having a somewhat differentarrangement of input and output ports (or light sources and detectors)within a flexible probe 403. Here, light port OP₁ functions as an outputport (associated with the illumination assembly), light ports OP₂ andIP₁ function as respectively output and input ports (associated with theillumination and detection assemblies), and light port IP₂ functions asan input port (associated with the detection assembly).

In the examples of FIGS. 1A-1C, the acoustic output port 245 (ortransducer arrangement) is located between the light input and outputports. It should, however, be understood that the acoustic port 245 maybe placed at any location on the flexible probe 403 (i.e. to the rightof light output port OP or the left of light input port IP). Severalacoustic output ports, at different locations along the flexible probe403, may be used being coupled to the same transducer arrangement or todifferent transducer arrangements. It should also be understood thatacoustic port 245 may be located outside the flexible probe 403, beingcarried by its own support structure configured for attaching to thebody part (e.g. skin).

When different acoustic transducer arrangements are used, the transducerarrangements may generate acoustic waves of the same frequencymodulation, or each may generate a different frequency modulation. Whendifferent frequencies are being generated, the control unit 120 controlsthe modulation at each transducer arrangement according to the spatiallocations of each output port associated with each transducerarrangement, such that light propagating through the same volume as thatof the acoustic waves propagation and collected through one or severallight input ports is analyzed based on the correct frequency modulationof the corresponding transducer arrangement (as will be described belowfor one such transducer arrangement). Different transducer arrangementscan generate acoustic waves at the same time intervals, or duringdifferent time intervals.

As indicated above, a region of interest can be identified by themeasurement system 100. This is carried out during the system operationin a calibration mode. Acoustic beams generated by the transducerarrangement or by a plurality of such arrangements, irradiate aplurality of body part regions underlying the probe 403, for exampleusing a phased array for scanning through different regions.Simultaneously, photons are introduced by the illumination assembly toirradiate the body part. Scattered photons are detected by detectionassembly. The control unit 120 analyzes tagged and untagged lightsignals associated with each region, as described above and will beexemplified more specifically further below. The processed signals arethen used to determine a parameter of each region. Determined parametersmay be compared to reference data to identify the region of interest.For example, a threshold value is defined (prior to applying the actualmeasurements) for a blood clot or a hemorrhage occupying a predefinedvolume within a region of interest. The measured parameters are thencompared to the threshold value. Region of interest is identified as aregion having a determined parameter with a higher value (or lower, orequal with a certain margin) as compared to the threshold. As anotherexample, a different threshold value is defined for an ischemic volumewithin a region of interest. Determined parameters are then compared tothe threshold to determine a region of interest.

The measurement system 100 can be operated to identify a region ofinterest having a predetermined scattering coefficient. The optimalpositioning of the illumination, detection and acoustic assemblies,having a plurality of input and output ports, can be determined byscanning an acoustic beam over different locations inside the body anddetermining for example the autocorrelation or power spectrum of signalsgenerated by each detection unit in response to photons scattered fromdifferent volumes within the body region overlapping with the acousticbeam. As the line-width of the autocorrelation or power spectrum of thetagged signals (frequency modulated), around the frequency of theacoustic radiation, depends on the scattering coefficient of the taggedvolume, the control unit can operate to monitor the line width, when theultrasound beam is used to optimally tag a volume having predeterminedscattering properties (e.g. a fluid reservoir such as a blood pool orextravascular fluid).

A region of interest may also be defined by the system operator (e.g.,defining region boundaries), and parameters indicative of this regioncan be recorded by the control unit 120. Control unit 120 determinesdistances between the region of interest and the acoustic output port245 and light input and output ports. Thus, the control unit 120determines an appropriate distance to be provided between the lightoutput port and the light input port, such that photons 250 from thelight output port will propagate through region of interest 200 beforereaching the input port IP. The control unit 120 can select which outputand input ports are used from a plurality of light ports arranged atdifferent spatial locations, such that at least one input port collectsphotons, emitted from at least one output port, that propagate throughthe volume of tissue through which acoustic waves 255 propagate. Withreference to FIG. 1B or FIG. 1C, the control unit 120 also determineswhich of the other light input ports (for example light input/outputport OP₂) collect(s) photons that propagate through surrounding tissues11 and not tissue region 200.

Additionally, during the calibration mode, the control unit 120determines a desired frequency bandwidth Δf₁ that is to be used duringthe measurements. As indicated above, the control unit 120 may determinethe desired frequency bandwidth Δf₁ to be used during the measurementsas that corresponding to a frequency bandwidth optimally filtered byanalog or digital electronic filters connected to the light detectors.The bandwidth that these filters optimally transmit is fixed or variedby the control unit 120 during the system operation. The control unit120 controls a portion of the frequency bandwidth generated by thefunction generator 122 to correspond to the frequency bandwidth that isoptimally transmittable by the electronic filters connected to the lightdetectors. Alternatively, the bandwidth of the filters is varied by thecontrol unit 120 to correspond to a portion of the frequency bandwidthgenerated by the function generator.

Following the calibration mode, the control unit 120 operates selected,fixed output and input light ports by modulating (including time gating)the light sources connected only to the chosen output ports, ormodulating the output ports themselves, and analyzing the signalsgenerated by the detectors coupled to the chosen input ports.

The control unit 120 controls the time dependent generation of thefrequency modulated acoustic waves. The control unit 120 furtherdetermines a time period Δt₁ needed for signal acquisition such thatoptimal signal-to-noise ratio (SNR) for determining a required parameter(e.g., oxygen saturation) is obtained during the measurements. The timeperiod Δt₁ is shorter than a time difference between the subject's heartbeats, when pulse oximetry is used for data analysis. The control unit120 also determines the frequency modulation parameters such that thedesired frequency bandwidth Δf₁, (or phase) propagates through thetissue volume 200 during the time period Δt₁. The onset of time periodΔt₁ is at time t₁ equal to about the time for a pulse generated atacoustic port 245 to reach tissue volume 200. Time t₂ is determined byt₂=t₁+Δt₁.

In the examples of FIGS. 1B-1C, the operation of apparatus 100 in a“monitor mode” or actual measurement mode is shown. Considering theexample of FIG. 1B, during the monitor mode, the control unit 120activates the light source(s) associated with the light output port OP₁to emit photons 250 and 251, and actuates the light source(s) associatedwith the output port OP₂ to emit photons 252. The light ports may beassociated with different light sources or with one or more common lightsource. A single light source and preferably two light sources, emittinglight of at least two different wavelengths, are connected to the outputports, whereas one light source may be connected to more than one outputport. Light sources connected to different output ports, or output portsthemselves, may be activated during different time periods and/or withdifferent characteristics (such as different modulation frequency orphase), such that the control unit 120 can distinguish between measureddata indicative of detected photons 251 and 252 collected by input portsIP₁ and IP₂ of the detection assembly.

The control unit 120 also activates the signal generator 122 that, inturn, activates the acoustic transducer arrangement 110 to generateacoustic waves 255 transmitted through the acoustic output port 245. Theacoustic wave frequency (or phase) generated by the function generator122 is modulated by the control unit 120 such that the acoustic wavesreaching region of interest 200 illuminated by photons 250 will have apredetermined frequency bandwidth Δf₁. If the bandwidth Δf₁ is fixed,then the control unit 120 determines the frequency modulation of thefunction generator controlling the generation of acoustic waves 255,such that acoustic waves 255 modulated at a frequency within Δf₁ reachtissue volume 200 at time t₁. In addition, acoustic waves with afrequency within Δf₁ substantially do not propagate through othertissues during the time period Δt₁ following time t₁. Accordingly, thecontrol unit operates the detection assembly 102A such that the lightdetectors associated with the input ports IP₁ and IP₂ start collectionof photons at time t₁ and end the collection process during time t₂.Alternatively or additionally, the control unit 120 controls theactivation of light sources associated with the output ports OP₁ and/orOP₂ at time t₁ and ends the activation at time t₂. During the timeperiod Δt₁, input port IP₂ and/or input port IP₁ collect photons 250propagating through the same tissues through which acoustic waves 255propagate (a time delay in photon propagation through the tissue, whichis on the order of a nanosecond, is neglected). Photons 251 essentiallydo not propagate through same tissue region through which acoustic waveshaving a frequency within Δf₁ propagate during time period Δt₁.

Reference is made to FIG. 1E more specifically describing an example ofthe system operation and data processing procedure considering thesystem configuration of FIG. 1B or 1C. The input port IP₂ receivesphotons 250 including tagged and untagged photons scattered by thesurrounding tissues 11 and tagged photons scattered by the tissue volumeof the region of interest 200, while the input port IP₁ receivesprimarily only untagged photons 251 scattered by surrounding tissues 11.A signal that is generated by the detection assembly 102A in response tophotons 250 collected at input port IP₂ is referred to as “signal A”. Asignal generated by the detection assembly 102A in response to photons251 collected at input port IP₁ is referred to as “signal B”.

According to this example, two models are selected to describe thepropagation of light in a multi layer tissue body. Such models aredescribed for example by Keinle et al. in Physics in Medicine andBiology 44: 2689-2702 (1999). One model (Model A) includes theparameters representing some of the tissues through which photons 251propagate from the output port OP₁ through a medium until they reach theinput port IP₁, and the other model (Model B) includes the parametersrepresenting some of the tissues in the medium through which taggedphotons 250 propagate until they reach input port IP₂. The modelsinclude known parameters, such as the molar absorption and scatteringcoefficients of blood cells, and of oxygenated hemoglobin anddeoxygenated hemoglobin at each of the wavelengths of illuminatingphotons. In addition, the models may include the thickness of thelayers, presence and volume of fluid in the light path and otherparameters that are measured during the operation of apparatus 100. Sometissue parameters in the model may be averaged or other manipulations ofthe known or measured parameters of the real tissues in models A and Bmay be carried out.

Given a certain amplitude of illuminating light, and the knownseparation between the light output port OP₁ and the input port IP₁,model A is used to calculate the expected time dependent photon flux, orlight intensity at the input port of the detection assembly 102A. Theexpected time dependent photon flux or light intensity is used tocalculate the expected signal (termed “signal C”) that can be generatedby the detection assembly 102A in response to such a photon flux. SignalC actually presents theoretical data for untagged photons at thelocation of detection assembly 102A, while signal B presents realmeasured data for untagged photons collected by the detection assembly102A.

The parameters of model A are adjusted (optimized) such that signal C ismade equal to or closely resembles signal B (best fitting). Signalprocessing techniques based on optimization algorithms, such as neuralnetwork, can be used to optimally determine the parameters of model A.The parameters are used to calculate the optical properties of some ofthe tissues through which photons 251 propagate.

It may generally be assumed that the optical properties of tissuesoutside the region of interest (i.e., within regions 11) through whichboth photons 250 and 251 propagate are similar. Alternatively, it may beassumed that by determining the parameters and optical properties of thetissues through which photons 251 propagate, one can deduce, within areasonable error, the optical properties of corresponding tissuesthrough which photons 250 propagate. The parameters calibrated by signalB and the optical properties of the tissues through which photons 251propagate are then used to calibrate (optimize) model B that describesthe propagation of photons 250 through surrounding tissues.

The time dependent amplitude of signal A at all wavelengths of photons250 is processed by the control unit 120 using techniques known in theart, such as digital Fourier transformations and analog or digitalfiltering, to extract, from the entire signal A, a signal portioncorresponding to the tagged photons 155. This signal portion is termed“tagged signal A”. Tagged signal A is that modulated at the acousticfrequency generated by the transducer arrangement 110. The amplitude ofthe power spectra of the tagged signal A at the acoustic frequency (orrelated to the acoustic frequency), the modulation width of its powerspectra or other features of tagged signal A, such as its phase, aretermed together as “processed tagged signal A” This processed taggedsignal A is actually indicative of both the surrounding tissues responseand the response of the region of interest tagged by the acousticradiation. In addition, the signal A contains information which is notmodulated at the acoustic frequency, termed “untagged signal A”.

According to this specific embodiment, untagged signal A may also beused in the data processing and analyzing procedure, for example todetermine some of unknown parameters of model B and further optimizethis model.

As indicated above, the control unit 120 processes the measured data(using an appropriate algorithm according to the type of detection used)to extract the measured data portion indicative of tagged photons, andprocess this data portion to identify a light response of region 200(photons scattered at region 200) by determining a relation between thetagged signals corresponding to different effective pathlengths of thetagged photons.

Using the above-indicated, or other suitable techniques, it is possibleto determine the effective attenuation of photons as they propagatethrough the region of interest. To this end, acoustic radiation may beapplied such that acoustic waves 255 propagate through different depthsof tissues (e.g., by displacing the transducer arrangement with respectto the body or by using a phase array transducer). Accordingly, theabsorption coefficient and the reduced scattering coefficient can beisolated for the two wavelengths chosen for illumination. For example,using a similar equation to equation 4 of the above-indicated Lev et al.reference:

$x = \frac{\gamma_{6}^{O} - {\frac{\mu_{{eff},6}}{\mu_{{eff},8}}\gamma_{8}^{O}}}{\lbrack {( {\gamma_{8}^{H} - \gamma_{8}^{O}} ) - {\frac{\mu_{{eff},6}}{\mu_{{eff},8}}( {\gamma_{6}^{H} - \gamma_{6}^{O}} )}} \rbrack}$

it is possible to determine the oxygen saturation level of the region ofinterest. Here, x is the fraction of deoxyhemoglobin, γ are the molarextinction coefficients of oxyhemoglobin (O) and deoxyhemoglobin (H) atboth wavelengths (in the referenced paper, 6 stands for 690 nm and 8 for820 nm) and μ_(eff,6) and μ_(eff,8) are the measured attenuationcoefficients at 690 and 820 nm, respectively.

The acoustic transducer arrangement 110 (or its output port) is kept ata specific location, which is optimal for propagating acoustic wavesthrough the same volume tissue from which scattered photons are detectedby the detection assembly. The beam size of transducer 110 is such thatthe cross section volume between photons and acoustic waves isdetermined by control unit 120 to achieve a high signal to noise ratio(SNR).

The control unit 120 analyzes both back and forward scattered taggedphotons to determine the optical attenuation of light propagatingthrough the region of interest. Consequently, the control unit 120 needsnot perform high resolution imaging of the region of interest, butrather analyzes the collected photons scattered within a significantvolume of the targeted tissues.

The control unit 120 processes that portion of the measured data, whichis associated with tagged photons 250 scattered from the region ofinterest, to determine the desired parameter of the region ofinterest—oxygen saturation in the present example. Two modalities canoptionally be used to determine the oxygen saturation level, one beingbased on measuring the average oxygen saturation level (known asoximetry) and the other being based on measuring the oxygen saturationlevel correlated with changes in the blood volume during the cardiaccycle (known as pulse oximetry).

Oxygen saturation S is a ratio between the concentration of oxygenatedhemoglobin [HbO] and the total concentration of hemoglobin [HbT] inblood:

S=[HbO]/[HbT](*100%)  [1]

[HbT]=[HbO]+[Hb]  [2]

wherein [Hb] is the concentration of deoxygenated hemoglobin.

The saturation S can be extracted from the attenuation coefficientmeasured for at least two wavelengths λ₁ and λ₂, where the molarabsorption and scattering coefficients for Hb and HbO at each wavelengthare known in the literature. It should be noted that more than twowavelengths can be used, to improve sensitivity of the measurement.

As the arteries expand, a blood volume [HbT] is increased by [AHbT],therefore absorption changes periodically. The optical attenuation at λ₁and λ₂ is measured at predetermined points (for example, the maxima andminima of a power spectrum of the tagged signal or the processed taggedsignal, as defined below) generated by the detection assembly 102Aduring a cardiac cycle. The saturation S can be calculated fromdifferences in attenuation of light (ΔOD^(λ)) at each wavelength betweenmaxima and minima.

ΔOD ^(λ)=(γ_(HbO) ^(λ) [ΔHbO]+γ _(Hb) ^(λ) [ΔHb])L ^(λ)=(γ_(HbO) ^(λ)S+γ _(Hb) ^(λ)(1−S))[ΔHbT]L ^(λ)  [3]

wherein γ_(HbO) ^(λ),γ_(Hb) ^(λ) are the molar attenuation coefficientof oxygenated and deoxygenated hemoglobin respectively, at wavelength λ(λ=λ₁,λ₂), L^(λ) is the effective optical pathlength from theillumination assembly (its light output port) to the detection assembly(its light input port), which accounts for tissue scattering. The factorL^(λ) can be estimated by solving the photon diffusion equation for theappropriate measurement geometry (for example as disclosed in A.Zourabian et al. “Trans-abdominal monitoring of fetal arterial bloodoxygenation using pulse oximetry” Journal of Biomedical Optics 5(4),391-405 (2000)).

Defining the ratio R between ΔOD^(λ) at each wavelength λ₁ and λ₂,assuming L^(λ1) substantially equals L^(λ2), we get:

$\begin{matrix}{R = {\frac{\Delta \; O\; D^{\lambda \; 1}}{\Delta \; O\; D^{\lambda \; 2}} = \frac{\lbrack {{\gamma_{{Hb}\; O}^{\lambda \; 1}S} + {\gamma_{Hb}^{\lambda \; 1}( {1 - S} )}} \rbrack}{\lbrack {{\gamma_{{Hb}\; O}^{\lambda \; 2}S} + {\gamma_{Hb}^{\lambda \; 2}( {1 - S} )}} \rbrack}}} & \lbrack 4\rbrack\end{matrix}$

where saturation S is extracted from equation [4] when ΔOD^(λ1) andΔOD^(λ2) are measured and the molar attenuation coefficients are known.In cases L^(λ1) does not substantially equal L^(λ2), it can bedetermined empirically (see above reference A. Zouràbian et al), orwavelength selection is determined such that the two parameters aresubstantially equal.

When monitoring a tissue region, or when there is negligible pulsation,ΔOD^(λ) is determined as the difference in a parameter of the opticalsignal between two different measurement conditions as defined below.

According to an embodiment of the present invention, the control unitanalyzes signals generated by the detection assembly in response to eachwavelength λ₁, λ₂ generated by the illumination assembly. The taggedsignals corresponding to collected tagged photons are selected by thedetection assembly using the principles of interference with a localoscillator, or by the control unit 120 using frequency analysis and/orspeckle imaging. The time dependent amplitude and/or phase of the taggedsignals for each wavelength λ₁, λ₂ is stored in the memory of thecontrol unit 120, over a specified period of time determined to optimizethe output signal, e.g. increase the SNR. To determine the oxygensaturation level of the region of interest, the control unit 120determines the time dependent changes in attenuation of tagged signalsat each wavelength.

Considering the determination of oxygen saturation of a region ofinterest 200 based on oximetry, the time averaged signals generated bythe detection assembly in response to the tagged photons of at least twoilluminating wavelengths collected by the light input port, are used todetermine the oxygen saturation level. Time averaging can be performedover longer time scales than the duration of a heart cycle.

When considering pulse oximetry used for determining oxygen saturationlevel, the temporal changes (due to the cardiac cycle) in the bloodvolume are monitored by the control unit 120 by monitoring thelow-frequency changes (0.5-2.5 Hz) in the signals generated by thedetection assembly in response to the tagged photons of at least twoilluminating wavelengths reaching the light input port of the detectionassembly. Since the ultrasound frequency is orders of magnitude higherthan the heart rate, it is possible to average the signals responsive totagged photons over a fraction of the heart cycle to improve the SNR ofthe measurement. Using methods of pulse oximetry, both the oxygensaturation and the pulse rate are determined simultaneously.

The control unit 120 displays the determined oxygen saturation level,along with heart rate, as a function of time. The heart rate isdetermined by low-frequency analysis of the tagged signals. The controlunit 120 optionally alerts using a suitable indication utility (e.g.sound and/or light signal), when oxygen saturation level drops below acertain threshold (for example 50% or 70%)

In an embodiment of the present invention, the optical unit isconfigured as a pulse oximeter, namely includes illumination assembly101A configured to generate light of at least two different wavelengthsand light detection assembly 102A; and is used in combination withacoustic transducer arrangement 110 to significantly improve the pulseoximetry measurements. The measurement system may be configured tooperate in a transmission mode (light transmission based detection),such as the conventional pulse oximeter placed on a finger or earlobe.In this case, support structure 403 is located such that illuminationassembly 101A is co-linear with detection assembly 102A: illuminationassembly 101A is placed at one side of the tissue and detection assembly102A is placed at the opposite side of the tissue, therefore ballisticand scattered light emitted from illumination assembly 101A are detectedby detection assembly 102A. Transducer arrangement 110 is placed suchthat acoustic waves overlap with an illuminated region in the region ofinterest from which scattered light reaches detection assembly 102A,which is preferably the region encompassing a blood vessel (e.g. anartery) or a collection of arterial vessels. In other applications,requiring reflection based detection from a region of interest(“reflection mode”), measurement system 100 is located as describedabove, where the region of interest preferably encompasses a bloodvessel (e.g. an artery) or a collection of arterial vessels. Such anarrangement is superior to conventional pulse oximeter as it is notaffected by incoherent ambient light, and more important is lessaffected by motion of the tissue relative to illumination and detectionassemblies, as long as the region of interest is kept illuminated andthe acoustic waves propagate through it.

It should be understood that using the acoustic tagging of light in thepulse oximetry based measurements significantly improves themeasurements, since the measured tagged light signal is practicallyinsensitive to movements of the region of interest under measurements,which is the common problem of the typical pure pulse oximetrymeasurements.

As indicated above, the at least two different effective pathlengths ofscattered tagged photons are achieved by appropriately operating theacoustic transducer arrangement with at least two different measurementconditions (corresponding to two different values of a characteristic ofacoustic radiation). Considering the oxygen saturation measurements,this provides for determining the oxygen saturation level of a region ofinterest without depending on the pulsating blood volume. This isparticularly important for measuring regional tissue oxygenation, orvenous oxygenation or when pulsation is negligible. Control unit 120controls the measurement conditions by controlling at least oneactivation parameter of transducer arrangement 110, such that transducerarrangement 110 emits at least two different acoustic signals having twodifferent activation parameters during the illumination of the region ofinterest by a single wavelength or by each one of at least two differentwavelengths of light (or vice versa). The at least one activationparameter includes but is not limited to the following: duration ofacoustic pulse or burst of waves, amplitude, frequency, number ofelements activated in a phased array, focal length of the transducerarrangement, focal dimensions (e.g. acoustic beam waist at focaldistance) of the transducer arrangement or gradient of chirp infrequency of the acoustic waves.

The measurement conditions are determined such that the tagged volume ineach measurement is within the region of interest, and that the averageoptical and acoustic characteristics of the tagged volumes are about thesame during and in between the two measurements. It is clear that two ormore measurements conditions can be changed between measurements. Forexample, two sets of measurements are taken with two different pulsedurations, where the first set has one acoustic wave amplitude and thesecond set is at a second acoustic wave amplitude. All measurements arethen used to determine a parameter of the region of interest.

Let us consider a signal generated by detection assembly 102A indicativeof the light response of the tagged volume:

I _(t)(t)=C|E _(U)exp[i(ω_(L) t+φ _(U))]+E _(T)exp[i((ω_(L)+Ω_(US))t+φ_(T))]|²  [5]

wherein C is a proportionality constant depending on the efficiency ofthe detection assembly and the area of the light input port IP, E_(U) isthe absolute amplitude of the untagged electromagnetic field, E_(T) isthe absolute amplitude of the tagged electromagnetic field, ω_(L), isthe light frequency, φ_(U) and φ_(T) are the phases of the untagged andtagged electromagnetic fields respectively, and Ω_(US) is the acousticfrequency.

As the tagging efficiency (the number of tagged photons relative to thenumber of untagged photons scattered by scattering centers inside thetagged volume) is small (i.e. I_(U)=|E_(U)|²>>|E_(T)|²=I_(T)), thedetected signal I_(t)(t) can be written as:

I _(t)(t)=C(|E _(U)|² +|E _(T)|²+2E _(U) E _(T) cos(Ω_(US)t+(φ_(U)−φ_(T))))≅I _(U) +I _(UT)  [6]

The first term is a DC component, whereas the second term is modulatedat the acoustic frequency. The amplitude of the second component,sampled at the acoustic frequency, divided by the DC component gives:

$\begin{matrix}{\frac{I_{UT}( {@\Omega_{US}} )}{I_{U}} = {\frac{2E_{T}}{E_{U}} = {2\sqrt{\frac{I_{T}}{I_{U}}}}}} & \lbrack 7\rbrack\end{matrix}$

The optical attenuation OD^(λ) of light at a specific wavelength λ isdefined by the modified Beer-Lambert law as:

$\begin{matrix}{{O\; D^{\lambda}} = {{\frac{- 1}{2.3}{\ln \lbrack \frac{I^{\lambda}}{I_{0}^{\lambda}} \rbrack}} = {{\alpha^{\lambda}L^{\lambda}} + G}}} & \lbrack 8\rbrack\end{matrix}$

wherein I^(λ) is the output intensity of light, I₀ ^(λ) is the inputintensity of light, α^(λ) is the absorption at wavelength λ (thatdepends on the concentration of the chromophores), L^(λ) is theeffective optical pathlength which accounts for scattering and G is ageometrical measurement factor.

For the tagged and untagged signals, using equation 8 we can write:

I _(T) =C ₁ I ₀exp└−α^(λ) L _(T) ^(λ) −G┘≡C ₁ I ₀κ_(T) ^(λ)exp[−G]  [9a]

I _(U) =C ₂ I ₀exp└−α^(λ) L _(U) ^(λ) −G┘≡C ₂ I ₀κ_(U) ^(λ)exp[−G]  [9b]

wherein C₁ and C₂ are constants, and L^(λ) _(T) and L^(λ) _(u) are theeffective optical pathlengths of the tagged and untagged photonsrespectively. Assuming that changes in the effective pathlength oftagged photons (ΔL_(T)) within the tagged volume depend primarily on thechanges in the characteristics of the acoustic radiation and areessentially independent on the wavelength of light:

$\begin{matrix}{\frac{\Delta \; \kappa_{T}^{\lambda}}{\kappa_{T}^{\lambda}} = {- \lbrack {{\Delta \; \alpha^{\lambda}L_{T}^{\lambda}} + {\alpha^{\lambda}\Delta \; L_{T}}} \rbrack}} & \lbrack {10a} \rbrack \\{\frac{\Delta \; \kappa_{U}^{\lambda}}{\kappa_{U}^{\lambda}} = {{- \Delta}\; \alpha^{\lambda}L_{U}^{\lambda}}} & \lbrack {10b} \rbrack\end{matrix}$

In equations 10a and 10b it is assumed that the effective opticalpathlength in the tagged volume is changed, whereas the effectiveoptical pathlength in the untagged volume is unchanged, and that thetagged volume is much smaller than the untagged volume, and thus achange in the effective optical tagged pathlength has negligible effecton the untagged signal. As Δα^(λ) represents changes in theconcentration of the chromophores in the media, it can be neglectedduring the measurement where there is negligible changes in theirconcentrations (i.e. when there is no pulsation in case of blood relatedmeasurement, or when the changes in the chromophores concentration occurover a much longer time scale then is accepted by the measurementconditions).

Thus, by introducing a change in the at least one characteristic of theacoustic radiation (e.g., resulting in a change in the effective opticalpathlength within the tagged volume) in between two consecutivemeasurements, the absorption coefficient of the chromophores within thetagged volume can be determined.

The tagged signal, extracted from the measured signal during the firstmeasurement is marked I_(T1), and the tagged signal during the secondmeasurement is marked I_(T2). Thus:

$\begin{matrix}{\frac{I_{T\; 1} - I_{T\; 2}}{I_{T\; 1}} = {\frac{( {\kappa_{T\; 1}^{\lambda} - \kappa_{T\; 2}^{\lambda}} )}{\kappa_{T\; 1}^{\lambda}} = {\frac{\Delta \; \kappa_{T\; 1}^{\lambda}}{\kappa_{T\; 1}^{\lambda}} = {\alpha^{\lambda}\Delta \; L_{T}}}}} & \lbrack 11\rbrack\end{matrix}$

For the case of oxygenated and deoxygenated hemoglobin α^(λ)=(γ_(HbO)^(λ)[HbO]+γ_(Hb) ^(λ)[Hb])=(γ_(HbO) ^(λ)S+γ_(Hb) ^(λ)(1−S))[HbT] for twodifferent wavelengths λ₁ and λ₂ we get:

$\begin{matrix}{R = {\frac{\alpha^{\lambda \; 1}\Delta \; L_{T}}{\alpha^{\lambda \; 2}\Delta \; L_{T}} = \frac{( {{\gamma_{{Hb}\; O}^{\lambda \; 1}S} + {\gamma_{Hb}^{\lambda \; 1}( {1 - S} )}} )}{( {{\gamma_{{Hb}\; O}^{\lambda \; 2}S} + {\gamma_{Hb}^{\lambda \; 2}( {1 - S} )}} )}}} & \lbrack 12\rbrack\end{matrix}$

Hence, Eq. 12 is equivalent to Eq. 4. Therefore inducing small changes(ΔL_(T)<<L^(λ) _(T)) in the effective optical pathlength of the taggedphotons in order to determine the oxygen saturation level within thetagged volume is equivalent to chromophore concentration change.

The following are non limiting examples of introducing a change in atleast one characteristic of acoustic radiation.

The control unit operates to control generation of the acousticradiation to create a tagged volume V_(T), such that small changes inV_(T) correspond to small changes in the effective optical pathlength oftagged photons. According to the present invention, the different taggedvolumes substantially overlap in space.

For example, the control unit operates to control the activation of asignal generator (122 in FIG. 1A), such that the signal generatortransmits two bursts (or pulses) with the same or different repetitionrate for each burst. This is exemplified in FIGS. 2A and 2B; an exampleof a measurement method is shown as a flow diagram in FIG. 3. Forclarity, only relevant elements of the measurement system 100 overlayinga region of interest 200 are shown in FIG. 2A-2B.

A control unit (not shown) activates a signal generator to produce anacoustic burst with a specific amplitude A, frequency F and phase φ. Thegenerated pulse activates the transducer arrangement at time t₁₀₀ forduration T₁. This burst, termed “T₁ burst”, propagates throughsurrounding tissues in the body part and reaches a region of interest200 at time t₀. The control unit activates an illumination assembly 101Ato emit light of at least one wavelength λ₁. The control unit activatesthe collection of signals from a detection assembly 102A at time t₀following t₁₀₀. Detection assembly 102A collects tagged and untaggedlight coming from the body part during time T₀. During time T₀(following time t₀), acoustic waves have propagated a distance D fromacoustic output port 245. The spatial length, d₁, of burst T₁ is equalto the product T₁·C_(s) where C_(s) is the speed of acoustic wavepropagation (e.g., speed of sound) in the region of interest. A volume266 that is been tagged by burst T₁ at any point in time is equal to d₁times a cross section A′ of the acoustic beam. For example, a planaracoustic wave with a uniform cross section A′ may be assumed, thusvolume 266 is equal to V₁=T₁·C_(s)·A′. The control unit operates toanalyze the measured data (detected tagged and untagged signals) todetermine a parameter of the signal corresponding to the opticalattenuation (e.g. the amplitude of the power spectrum of the detectedsignal at the acoustic wave frequency). The determined parameter isstored in the memory utility

The control unit activates the signal generator to generate a secondburst having the same amplitude A, frequency F and phase Φ. Thegenerated pulse activates the transducer arrangement at time t₂₀₀ for aduration T₂ (T₂ being different from T₁). This burst, termed “T₂ burst”,propagates through the surrounding tissues in the body part and reachesa region of interest 200 at time t₀.

It is clear that a plurality of T₁ bursts can be emitted sequentiallyprior to emission of a plurality of T₂ bursts, as long as the opticaland acoustical properties of the tissues do not change during the twoseries of pulses. A series of signals each corresponding to a series ofT₁ and T₂ bursts will be analyzed as a long burst. In such cases it ispreferred that the burst of acoustic waves are phased locked in order toimprove SNR. The signals are concatenated, as to form a long timedependent signal, and then analyzed as being a result of one long burst.

Burst T₂ propagates the same distance D during time T₀ following timet₀. Burst T₂ occupies a volume 267 equal to: V₂=T₂·C_(s)·A′. For aplanar acoustic wave, the difference in the tagged volume is:ΔV_(T)=V₁−V₂=(T₁−T₂)·Cs·A′. The control unit also activates illuminationassembly 101A to emit light with at least one wavelength λ₁. The controlunit activates the collection of signals from a detection assembly 102Aat time t₀ following t₂₀₀.

The control unit activates the detection assembly 102A to collect taggedand untagged light signals for the duration T₀ being preferably shorterthan the shortest duration of the bursts (i.e. the smallest of T₁ orT₂). As the tagged volume is varied, the number of tagged photonsreaching the detector input port will vary. The control unit analyzesthe respective measured data to determine the same parameter of thesignal corresponding to the optical attenuation (as for burst T₁), andstores this parameter in the memory utility. Thus, for each burst T₁ andT₂, the control unit records the tagged and untagged signals, and storesthem in the memory.

The above technique is repeated for each wavelength λ₁, λ₂, and for eachwavelength the difference in the tagged signal (I_(T1)−I_(T2)) iscalculated from the difference in the tagged signal parameter (forexample, amplitude of tagged signal power spectrum at the acousticfrequency, being normalized or not by the untagged signal relevantparameter) between bursts T₁ and T₂, and equation 12 is used todetermine the oxygen saturation level.

As another example, the different operating conditions of acousticradiation generation (providing different effective optical pathlengths)are achieved by controlling the waist of the acoustic beam. The controlunit determines the waist of the acoustic beam by controlling a beamaperture or a number of acoustic elements activated in the transducerarrangement 110, forming a phase array. The focal distance of the arrayis unchanged in between bursts, and only the beam dimensions are variedin between the two bursts (i.e. one burst having beam waist BW₁ and theother BW₂). Similarly to the above-described example of different pulsedurations, here the tagged signal is determined for each waist BW₁ andBW₂ and the relative difference in parameters of the tagged signal isdetermined for each burst. The process is repeated for each of the atleast two illuminating wavelengths, and the parameter of the tissue isdetermined.

The tagging efficiency, defined as the number of tagged photons relativeto the number of untagged photons scattered by scattering centers insidethe tagged volume, is known to depend on the frequency of the acousticbeam, the speed of the acoustic wave in the tissue, and on the amplitudeof the acoustic radiation in the tagged volume. Therefore changes of thefrequency of the acoustic radiation, the intensity (or power) of theacoustic beam, and the speed of acoustic wave (sound) in the tissueaffect changes in the effective optical pathlength of the taggedphotons.

Assuming a constant tagging efficiency in between the two measurementconditions as explained above, the normalized amplitude at the acousticfrequency corresponds to the optical attenuation of the media. Assumingthat the average optical and acoustic properties of the illuminatedmedia are about the same in between the two measurements, the differenceor ratio between the optical attenuation at the two measurementconditions corresponds to the optical properties of the region ofinterest

The effective optical pathlength can also be varied in betweenmeasurements by varying the tagging efficiency.

As an example, the amplitude of the acoustic waves can be varied betweentwo or more acoustic bursts. For example, the transducer arrangementgenerates one burst with amplitude A₁ and the other with amplitude A₂different from A₁. As the tagging efficiency depends on the amplitude ofthe acoustic waves, measured data is indicative of two different taggedsignals generated by the detection assembly in response to collectedphotons at each burst of acoustic waves with amplitude A₁ and A₂. Thedifference or the relative difference between the two signalscorresponds to the effect of the acoustic waves' amplitude on the taggedsignals and can therefore be determined by this measurement.

As yet another example, the frequency of the acoustic waves is variedbetween two bursts (or two series of bursts) one having a frequency F₁and the other a second frequency F₂. In case of a focused acoustic beam,assuming no chromatic aberrations of an acoustic lens assembly used inthe transducer arrangement, the dimensions of the focal volume (i.e. thebeam diameter and length of the focal zone) are known to depend on thefrequency of the acoustic radiation. Consequently, different frequencieswill be focused into different volumes, and the volume of the taggedregion will be different for each frequency. In addition, the taggingefficiency depends on the frequency of the acoustic waves. Both effectsresult in a different effective optical pathlength. The control unitactivates the signal generator to emit bursts having the same amplitude,phase and duration, but two different frequencies F₁ and F₂. Thismeasurement scheme is repeated for each wavelength λ₁ and λ₂ ofilluminating light, and for each wavelength the difference inattenuation is calculated from the difference in the tagged signalparameter (for example, amplitude of the tagged signal power spectrum atthe acoustic frequency) between bursts having frequency F₁ and F₂, andEq 12 is used to determine the oxygen saturation level.

As yet another example, the acoustic frequency of each burst may bemodulated (for example having a chirp) such that the signal generatorgenerates continuously chirped signals (thus a “burst” refers to asingle cycle of chirping). The control unit determines frequency rangeΔf₁ as described above, to propagate through tissue volume 200 duringtime Δt₁ following time t₀. As exemplified in FIG. 2C, during one cycleof chirped cycles (cycle 1), the gradient of the chirping (∂f/∂t) isequal to GC₁ and during a second cycle of chirped cycles, the gradientof the chirping (∂f/∂t) is equal to GC₂.

The control unit activates an illumination assembly 101A to emit lightof at least one wavelength λ₁. The control unit activates the collectionof signals from a detection assembly 102A at time t₀. The process isrepeated for the different optical wavelengths for each set GC₁ and GC₂,and the processed signals (e.g. power spectrum of tagged signal) arestored in memory. Again, a parameter of the tagged and untagged signalis determined for each cycle GC₁ and GC₂, and stored in memory. Adifference between the normalized tagged signals is determined for eachwavelength as the difference in that parameter for each wavelength, forthe two cycles.

As the tagging efficiency depends on the acoustic properties, but theoverall tagged signal depends on both the optical and acousticproperties of the tagged volume, the different measurement conditionscan be used to decouple the effects of the tagging efficiency on theoverall signal. This is achieved, for example, by performing fourdifferent measurements, one pair indicative of two different pulsedurations with one amplitude, and the second having the same two pulsedurations at the other amplitude of acoustic waves. For each pair ofmeasurements Δα^(λ) is determined as above, and then the differencebetween the determined values (if exists) accounts for changes in thetagging efficiency. Once this dependence is established, it can be usedto determine the effect of the acoustic parameters on the measuredsignals. Alternatively, three different optical wavelengths can be usedto determine a relative measurement condition, where the acousticproperties are the same in between the measurements. The measurement isrepeated for each of the three wavelengths, at two different measurementconditions, and the acoustic properties are decoupled from thedetermined signals.

The following is an example of using the system of the present inventionfor imaging a tissue region in a body, namely mapping the opticalattenuation (i.e., determining the optical attenuation parameter at eachlocation). Control unit 120 operates ultrasound transducer arrangement110 to scan different tissue volumes. The intensity of each pixel orvoxel in the image is determined as follows:

Step 1: The signal generator 122 is activated to transmit a signal totransducer arrangement 110 to generate one acoustic burst T₁.

Step 2: The illumination and detection assemblies are activated at acertain time delay t_(d), such that acoustic burst T₁ propagated adistance D_(d) from acoustic port 245 which is determined asD_(d)=C_(s)·t_(d). In case transducer arrangement 110 is a phased array,then control unit 120 also determines the angle Θ_(d) between theacoustic port 245 and the acoustic beam propagation direction. Controlunit 120 processes and analyzes signals (measured data) generated bydetection assembly 102A during time T₀ (as defined above), and storesparameters of processed signals in memory.

Step 3: Step 1 and Step 2 are repeated using the same time delay t_(d)parameter (and angle Θ_(d) parameter, where applicable) while ultrasoundburst T₂ is generated by acoustic arrangement 110.

Step 4: Control unit 120 then analyzes the stored parameters oflight-indicative signals generated during bursts T₁ and T₂ to determinea property of the tissue volume being tagged by acoustic radiation atdistance D_(d) (and angle Θ_(d), where applicable) from the acousticport. A certain value is then assigned to the so-determined property(for example degree of oxygen saturation of that volume).

Step 5: The assigned value is displayed as a two or three dimensionalimage on a display, where the location of the pixel/voxel corresponds tothe distance D_(d), and angle Θ_(d) from acoustic port 245 (the locationof acoustic port 245 may serve as the “zero position” on the displaywhere all the distances are calculated relative to that zero position).

Steps 1-5 are repeated for different delays t_(d) (and different anglesΘ_(d)) and a full image is displayed, where the value of each pixel istranslated to a color scale, a grey level scale or a numerical scalerepresenting the value of a parameter (such as hemoglobin concentrationor oxygen saturation).

The technique of the present invention can be used to determine theconcentration of blood or the volume of blood or other chromophoreswithin the region of interest. For determining the blood volume, asingle wavelength corresponding to the isosbestic point of oxygenatedand deoxygenated hemoglobin can be used, but preferably two or threewavelength of light are used, whereas at least one corresponds to theisosbestic point. For determining blood volume or concentration withinthe tagged volume, two characteristically different bursts of acousticwaves are generated by transducer arrangement (as described above foroxygen saturation). For each burst, the tagged signals and the untaggedsignals are detected and corresponding measured data is collected by thecontrol unit during a time period corresponding to the propagation ofthe acoustic waves inside the region of interest. The signals arerecorded and stored in memory for each wavelength of light. For theisosbestic point, γ_(HbO)=γ_(Hb)≡γ_(HbT), and from equation 12 above, weget:

ΔOD ^(λ)=γ_(HbT) ^(λ) [HbT]ΔL _(T)  [13]

The total volume of blood within the tagged volume can be calculated ifΔL_(T) is known. Preferably, two or more wavelengths are used todetermine the concentration of hemoglobin in the region of interest, asexplained above.

It is known that the optical properties of a blood clot or an internalhemorrhage can be determined by near infrared spectroscopy [B. Chance etal “Optical investigations of physiology: a study of intrinsic andextrinsic biomedical contrast” Phil. Trans. R. Soc. Lond. B (1997) 352,pp. 707-716]. Therefore, by monitoring the changes in the tagged signalsfrom a region of interest within a hematoma or a hemorrhage, the controlunit can operate to determine a hemorrhagic event, and possibly thetime-span of a hemorrhage, or changes in the blood volume of an existinghemorrhage.

According to another embodiment of the invention, the region of interestis a blood vessel or blood-filled cavity such as a ventricle, sinus orbulb. Oxygenation of blood inside the region of interest is monitoredusing a measurement system of the present invention. For example, venousoxygen saturation is measured in the Jugular vein bulb using a modifiedprobe. The Jugular vein bulb is located at the base of the skull, about2-3 cm behind the ear canal. It is therefore advantageous to place anacoustic transducer arrangement inside the external ear canal, such thatits output face forms acoustic contact (using a gel or oil) with theouter walls of the external ear canal. The transducer arrangement isconfigured and positioned such that acoustic waves travel through theear canal and are focused on the jugular vein bulb. This configurationmay include phased array elements, or other elements that are arrangedto be operated in any direction, phase or time delay. In order todetermine precise location of the Jugular vein bulb, relative to the earcanal, the operator may rely on radiographic images acquired prior tooperation of the imaging apparatus or on back reflected Doppler signalsfrom the bulb. When using Doppler signals, the transducer arrangement,may include, inter alia, an acoustic transducer capable of generatingand collecting acoustic signals having an appropriate frequency andduration for performing Doppler measurements (for example usingultrasound waves frequency of 2 MHz). A control unit analyzes theseDoppler shifted signals to determine distance from probe head located inthe ear canal to the Jugular vein bulb during the calibration mode, andalso in between actual measurements to verify that the acoustictransducer has not shifted relative to the Jugular vein bulb.

Reference is made to FIGS. 4A-4B exemplifying the use of a measurementsystem 100 of the present invention for measuring oxygen saturationlevel in a region of interest outside cerebral tissues. The region ofinterest is the internal jugular vein; in some cases the internaljugular vein bulb is located in the vicinity of the middle ear cavity.The region of interest is preferably located by using a Doppler imagingsystem capable of identifying blood flow direction and distance tovessel. Such a Doppler system may form part of a transducer arrangement110 of measurement system 100. Once the location of the jugular veinregion of interest is determined (either the bulb or another region),the transducer arrangement 110 is fixed in place using an adhesive thatis extracted from underneath an acoustic output port or using a belt. Aflexible probe (support structure) 403 is attached to the skin regionoverlaying the region of interest. The flexible probe 403 carries anillumination assembly 101A (at least light output ports thereof) and adetection assembly 102A (at least light input ports thereof) along withcorresponding index matching optical adhesives for securing thepositions of the input and output light ports. Flexible probe 403 isconnected to a control unit 120 using cables, optical fibers or wirelessmeans.

In the arrangement shown in FIG. 4A, transducer arrangement 110 islocated such that at least its output port is on the support structure403 in between light input and output ports. Control unit 120 operatesto determine a distance between the input and output light ports suchthat light propagating through the region of interest is collected bythe detection assembly 102A. In the system configuration of FIG. 4B, thetransducer arrangement 110 is placed external to the support structure403 in an optimal location for irradiating the jugular vein bulb or thejugular vein with acoustic radiation. Such an optimal location may bethrough the ear canal as disclosed above. The control unit (not shownhere) then determines the optimal position of illumination and detectionassemblies such that light scattered from the region of interest willreach the input port of the detection assembly 102A. The control unitcontrols the operation of the optical unit carried by the supportstructure 403 and the operation of the acoustic transducer arrangementso as to enable determination of the oxygen saturation of blood passingthrough the jugular vein. In addition, control unit may collect Dopplershifted acoustic signals being reflected from blood flowing inside thejugular vein to determine blood flow parameters as well as to adjust formovements or changes of the probe head relative to the region ofinterest.

It is understood by those skilled in the art that an acoustic transducerassembly can be inserted through other tracks or lumens inside the humanbody, such that it forms acoustic contact with an internal wall of thetrack.

According to yet another embodiment, one of the illumination ordetection assemblies may be inserted through the same track or lumen asthe transducer arrangement, or through a different track or lumen toprovide optimal positioning of the system relative to the region ofinterest. Such a configuration may include a catheter inserted into atrack or lumen or an endoscope carrying optical and acoustic means forimaging an internal part of the body.

It should also be noted that other blood vessels (veins or arteries) maybe monitored using this apparatus, and the measurement technique is notlimited to the jugular vein, given only as an example. Other examplesinclude but are not limited to monitoring other blood analytes in bloodvessels (such as glucose, urea and bilirubin) and monitoring othervessels (e.g. the femoral artery in the hip joint or at other locationswhere it is close to the skin). In each embodiment the blood vessellocation is determined using an imaging system (preferably a Dopplerimaging system) and the system of the present invention is used tomonitor the blood vessel.

Reference is made to FIG. 5A exemplifying a modified probe (measurementunit) 101 for measuring in a region of interest. Here, an illuminationassembly 101A includes one or more light emitter (not shown) and a lightguiding unit including light guides, optical fibers or fiber bundles 810and 814 optically coupled to each other by a coupler 850. Light fromlight emitter(s) is coupled into the fiber 810 at its one end, andpropagates through this optical fiber towards the optical coupler 850 tobe further coupled to optical fiber 814.

The distal end of fiber 814 presents a light output port OP of theillumination assembly. Also coupled to the optical coupler 850 is anoptical fiber or fiber bundle 811. A detection assembly 102A includesone or more light detectors (not shown) and a light guiding unitincluding an optical fiber or fiber bundle 812 optically coupled to anoptical fiber or fiber bundle 813 via an optical coupler 851, which isalso coupled to the fiber or fiber bundle 811.

The optical coupler 850 is appropriately configured to couple a certainfirst portion (for example 1% of propagating light intensity) of inputlight propagating through fiber 810 to optical fiber 811, and couplingthe other second portion of input light (e.g. 99%) into fiber 814. Thissecond portion of light from fiber 814 illuminates, through light outputport OP, a skin region 10 overlaying a region of interest 200. Fiber 813delivers light, collected by light input port IP, towards the lightdetector(s).

Coupler 851 couples light from fiber 813 and fiber 811 into fiber 812.Coupler 851 is designed to provide maximal transmission of light fromfiber 813 into fiber 812, meaning that there are minimal couplinglosses. The coupling efficiency of coupler 851 from fiber 811 into fiber812 should preferably be constant.

It should be understood that fiber portions 810 and 814 or fiberportions 813 and 812 can form the same physical fiber, and need not beseparate fibers. It should also be understood that the optical unit(i.e., the length of the fiber portion 811 and the position of couplers850 and 851 along fibers 810 and 813) is configured such that lighttraveling through fiber 811 is coherent with light, collected by inputport IP and arriving at coupler 851, so as to satisfy the interferencecondition. This requirement is consistent with the requirement that thecoherence length of the light source is longer than the path length oflight inside the tissue, as explained above. Couplers 850 and 851 can beincluded in the flexible probe 403.

As photons 820 from fiber 811 interfere with tagged and untagged photons250 propagating in fiber 813, the intensity of light reaching thedetector(s) is modulated in time.

The interference signal of three electromagnetic fields is beingdetected by the detection assembly. It can be written as:

I _(t)(t)=C|E _(U)exp[i(ω_(L) t+φ _(U))]+E _(T)exp[i((ω_(L)+Ω_(US))t+φ_(T))]+E _(LO)exp[i(ω_(L) t+φ _(LO))]|²  [14]

wherein C is a proportionality constant depending on the efficiency ofthe detection assembly and area of the light input port, E_(U) is theabsolute amplitude of the untagged electromagnetic field and E_(T) isthe absolute amplitude of the tagged electromagnetic field, ω_(L) is thelight frequency, φ_(U) and φ_(T) are the phases of the untagged andtagged electromagnetic fields respectively, Ω_(US) is the acousticfrequency, E_(LO) is the absolute amplitude of the referenceelectromagnetic field and φ_(LO) is its phase.

The signal can be divided into three components:

I ₁ =|E _(U)|² +|E _(T)|² +|E _(LO)|²+2E _(U) E _(LO) cos(φ_(U)−φ_(LO))

I ₂=2E _(LO) E _(T) cos(Ω_(US) t+φ _(T)−φ_(LO))

I ₃=2E _(U) E _(T) cos(Ω_(US) t+φ _(T)−φ_(U))  [15]

The first component, I₁, will mostly be at DC and will have a certainlinewidth that depends for example on the breathing rhythm of the bodyand on the Brownian motion of the scattering centers. The second andthird interference patterns are time modulated at the frequency ofacoustic waves 255 emitted by transducer arrangement 110. Control unit120 analyzes the signal generated by the detection assembly to determineparameters of the region of interest and of the tissues surrounding theregion of interest. All three components can be analyzed simultaneously.Additionally, each component can be separated by blocking transmissionof photons 820, or of photons 250, or by analyzing the detected signalswhen the acoustic waves are not propagating (no “tagging”).

For example, photons 820 can be used to determine light sourcecharacteristics by the control unit during the system operation. Thecontrol unit can activate coupler 851 to block transmission of lightfrom fiber 813 into fiber 812 at specific time periods. During theseperiods, only photons 820 are detected, and can serve as a reference forthe illuminating light properties (e.g. intensity, coherence length ofsource). According to another option, the control unit activatesdetection of photons 250, when acoustic waves 255 do not irradiate thetissues at all. Thus all of photons 250 are not tagged during theseperiods (“no tagging”). The signals detected during these periods resultfrom the interference of untagged photons 250 and photons 820. Thissignal depends for example on the Brownian motion of the scatteringcenters, and on breathing rhythms. Thus, these two parameters can bedetermined during these periods, and be used to optimize the measurementconditions (for example to reduce artifacts from breathing). The controlunit activates detection of photons 250 when acoustic waves 255 doirradiate the region of interest (“normal tagging”). When taggingoccurs, there is an increase in components number two and three,relative to the periods of “no tagging”. These relative changes canassist in determining parameters of the region of interest and ofsurrounding tissues.

According to yet another option, when acoustic radiation is used to tagthe region of interest (normal tagging), the control unit can blockcollection of photons 820 by blocking their transmission through coupler851, thereby sampling photons 250 (i.e. only the untagged light and thethird component). This signal is used to decouple the contribution of I₂to the signal modulated at the acoustic frequency (i.e. I₂+I₃) when bothphotons 820 and 250 interfere (termed “coupled signal”), and thusextract the contribution of I₃.

In order to simultaneously decouple the contributions of I₂ and I₃ tothe coupled signal, a frequency shift is preferably introduced in thereference arm formed by fiber 811.

FIG. 5B illustrates a similar configuration of a measurement unit 101,but utilizing a light modulator (e.g., acousto-optic modulator orphotorefractive crystal) 815 located in optical path of light passingthrough fiber 811. Light propagating through fiber 811 is coupled intothis light modulator through its entry face 811 a and is coupled out ofthe light modulator 815 through its exit face 816 a into another opticalfiber 816, which is in turn optically coupled to coupler 851. Coupler851 couples light from optical fibers 816 and 813 into fiber 812. Aslight propagates through light modulator 815, its frequency is shiftedby a certain frequency Ω_(AO) determined by a control unit (not shown)relative to the characteristic frequency Ω_(US) of acoustic radiationgenerated by a transducer arrangement 110. The modulation frequencyΩ_(AO) is optimally chosen to be different from the characteristicfrequency Ω_(US). Consequently, photons 820 are frequency shifted asthey exit modulator 815, and are denoted modulated photons 821. Asphotons 250, collected at light input port IP and coupled by coupler 851from fiber 813 to fiber 812, interfere with photons 821. Theinterference signal is:

I _(t)(t)=C|E _(U)exp[i(ω_(L)t+φ_(U))]+E _(T)exp[i((ω_(L)+Ω_(US))t+φ_(U))]+E _(LO)exp[i((ω_(L)t+Ω_(AO))t+φ _(LO))]|²  [16]

and it has four relevant frequency components:

I′ ₁ =|E _(U)|² +|E _(T)|² +|E _(LO)|²

I′ ₂=2E _(LO) E _(U) cos(Ω_(AO) t+φ _(U)−φ_(LO))

I′ ₃=2E _(LO) E _(T) cos((Ω_(US)−Ω_(AO))t+φ _(T)−φ_(LO))

I′ ₄=2E _(T) E _(U) cos(Ω_(US) t+φ _(T)−φ_(U))

As the number of photons 821 can be monitored, for example by blockingtransmission of photons 250 though coupler 851 and detecting the numberof photons 821 reaching the detection unit, the contribution of theuntagged photons to the first component I′₁, can be isolated, assuming,as before, |E_(U)|²>>|E_(T)|². The generated signals at three differentfrequencies represent, respectively, interference between photons 821and the untagged photons 250 (I′₂), interference between photons 821 andtagged photons 250 (I′₃), and interference of tagged and untaggedphotons 250 (I′₄). Since photons 821 do not pass through the body, thecontrol unit can extract effects related to the overall lightpropagation in the body tissues from light source to detector, and localeffects of the tagged volume separately.

For example, using the configuration of FIG. 5B, there are twoindependent measures for the tagged and untagged photons, allowingdecoupling of speckle correlation or Brownian motion of the scatteringcenters, from components I′₂ and I′₄. In addition, once the tagged anduntagged signals are decoupled, they can be used to calibrate tissuemodels A and B described above.

Thus, for example, the line width of component I′₂ can be used todetermine the scattering coefficient of the tissues. Consequently, thescattering coefficient of tissue models A and B can be determined andused to calibrate and account for light propagation though surroundingtissues. Following, control unit 120 determines the absorptioncoefficient of the region of interest, decoupled from the scatteringcoefficient, by measuring the attenuation of light through the tissue.

In addition, the relative amplitudes of the components I′₂, I′₃ and I′₄can be used to isolate the contribution of each signal. For example, theratio between the amplitudes of components I′₂ and I′₃ can be used tooptimize the modulation amplitude of component I′₃. This can be done bycontrolling the percentage of photons 820 that are coupled into fiber811 by coupler 850, or by controlling the transfer efficiency of themodulator 815, resulting in a control over the number and phase ofphotons 821. The number of photons 821 can be made, for example,approximately equal to the number of tagged photons 250 at eachwavelength by optimizing the amplitude of component I′₃. Once such acondition is achieved, component I′₃ will provide maximal sensitivityfor changes in the tagged photons signal.

As the line width of the autocorrelation or power spectrum of the taggedsignals, around the frequency of the acoustic radiation, is differentwhen tagging is performed in different media, the control unit candetermine, by monitoring the line width, when the ultrasound beam isused to optimally tag a volume of the region of interest.

Additionally or alternatively, other parameters of the tagged anduntagged signals, such as amplitude and frequency, are used to determineone or more parameter indicative of a region of interest. For example,the blood volume in each location may be determined as described above.Control unit then displays the blood volume at each location beingscanned by the acoustic beam. The display can be overlaid over amorphologic image of the organ being monitored, such as a CT or MRIimage of the brain. The system of the present invention can monitorcerebral hemorrhage, subarachnoid hemorrhage or other blood clots in thebrain. Alternatively, the oxygen saturation corresponding to eachlocation of the acoustic beam can be determined and displayed. Thesystem can be used to monitor tissue ischemia, in particular cerebralischemia.

In another embodiment of the invention, the measurement system may beused to monitor changes in the concentration of analyte(s) in a regionof interest during therapeutic or surgical procedures (such as duringthe application of high power ultrasound pulses or wave, laser ablation,or chemical procedures). For example, the transducer arrangement may beused for ablation of tumors or malformations in a tissue. During theapplication of high power ultrasound pulses, light is emitted andcollected by illumination and detection assemblies, respectively, todetermine the concentration of an analyte indicative of the treatment inthe region being ablated. Alternatively, low power ultrasound pulses(that do not cause ablation) intermittently irradiate the region ofinterest, while low-power light pulses are emitted and collected byillumination and detection assemblies to determine the concentration ofan analyte indicative of the treatment. For example, oxygenation of theregion of interest is monitored. Such information is used forcontrolling and monitoring the treatment during application ofultrasound radiation.

It should be noted that same acoustic or light radiation applied formonitoring parameters of a region of interest, according to anyembodiment of the present invention, can have therapeutic value. Forexample, acoustic radiation can improve thrombolitic activity of tPA(tissue Plasminogen Activator) or other thrombolitic agents. Therefore,the same acoustic radiation emitted by acoustic arrangement 110 havingat least on of the following parameters: the same intensity, amplitude,duration, frequency, repetition rate, phase or power, used formonitoring tissue parameters such as oxygenation, may also providetherapy to the region of interest.

Reference is made to FIGS. 6A-6B exemplifying specific designs suitablefor a transducer arrangement 110. In order to create a focusedultrasound beam, a phased array 410 comprising a plurality of elementsis used. Different configurations of a phased array having a largeeffective area without compromising the flexibility for positioning theillumination and detection assemblies are described.

FIG. 6A schematically shows a top view of transducer arrangement 410comprising an annular phased array, arranged to define a centralopening. The number and dimensions of annular acoustic elements410A-410D are determined to correspond to a predetermined focal depthand F# for the array. Transducer arrangement 410 is placed in acousticcontact with skin 401, overlaying a region of interest. Opticalelements, preferably optical fibers, associated with illumination anddetection assemblies are positioned inside the circular opening of thetransducer arrangement. Five such elements 420A-420E are shown in theFIG. 6A figure. Any one of these elements can serve as an input oroutput light port according to an embodiment of the present invention.Such a configuration allows for a tighter focused beam and a shallowerfocal depth than those achievable with a single element transducer, or aphased array being placed in between the input and output light ports.The phased array elements 410A-410D are activated by a control unit (notshown here) to provide a focused ultrasound beam at the region ofinterest, or outside the region of interest. The focal plane of thephase array can be scanned by introducing corresponding delays betweenthe activation of each annular element.

In the example of FIG. 6B, a partial annular phased array 415 ispresented. Array 415 is designed generally similarly to theabove-described array 410, and distinguishes from array 410 in thatacoustic transducers 415A-415A do not form closed annular elements, butare only partially concave. Array 415 has similar focal depth and F# asthe above-described array 410 (assuming these arrays have the samenumber of transducer elements and dimensions). Comparing the arraydesign 415 to array 410, the array 415 provides more flexibility inpositioning over skin areas which is required for example in thepresence of a bone underneath skin region 401.

Reference is made to FIGS. 7A-7B and 8A-8B exemplifying differentconfigurations of a support structure (probe) 403 suitable to be used inthe present invention. In the example of FIGS. 7A-7B, the flexible probe403 includes a flexible support 301, for example made of electricallyinsulating material(s), carrying light ports 303-316 (fiber-ends inappropriate housing, or light sources and/or light detectors asdescribed above) and an acoustic output port 302 (or acoustic transducerarrangement). FIG. 7A is a bottom view of the flexible probe 403 viewedfrom the side by which it is attachable to a skin, and FIG. 7B shows aside view diagram of the flexible probe 403.

Optical fibers or electric wires 330-336 and 340-346 connect the lightports 310-316 and 303-309, respectively, to a common connector 320. Aninsulated electric cable (or acoustic waveguides) connects the acousticoutput port 302 to the same connector 320. The acoustic port 302 ispreferably coupled to an acoustic transducer arrangement 327 connectedto the flexible support 301 using vibration controlling elements. Theconnector 320 is associated with a control unit (not shown), namely,couples the optical fibers and cables attached to the flexible support301 with optical fibers and electric cables coupled to the control unit.The connector 320 may be composed of several connector elements. Anadhesive 325 is attached to the bottom side of the support 301, suchthat the probe 403 can be fixed to the skin using this adhesive 325.Adhesive 325 is preferably light transparent and produces minimalscattering in a wavelength range used for measurements (i.e., emitted bylight sources). Alternatively or additionally, the adhesive 325 may forman optical index matching layer between the light ports and the skin.Alternatively, the adhesive 325 may not cover the light ports at all, ormay partially cover them. The adhesive 325 may contain pigments,chromophores or other materials for controlling the transmission ofdifferent wavelengths of light. An adhesive gel 326 is located below theacoustic port 302. The adhesive gel 326 is made from the same ordifferent material as the adhesive 325 and is designed for optimalacoustic coupling between the acoustic port 302 and the skin. Possiblematerials for adhesives 325 and 326 include hydrogel based adhesives.

The different elements of the flexible probe 603 may be assembled indifferent ways. For example, the complete probe 603 is assembled priorto operation, and a user only needs to remove a thin layer covering thebottom side of adhesives 325 and 326. In yet another example, theadhesive 326 is attached to the acoustic output port 302 (preferablyincluding the acoustic transducer arrangement itself) which is notattached to the probe 403 prior to the device operation. The user firstattaches the flexible support 301 to the skin using the adhesive 325,and then inserts the acoustic port 302 through an appropriately providedopening in the support 301, where the transducer 327 is optionallyconnected to the support 301 using conventional means and is attached tothe skin using the adhesive 326. The latter may be part of adhesive 325,and only the acoustic output port 302 is inserted and attached to theupper part of the adhesive 326 (being a double sided adhesive). The userfirst attaches the adhesives 325 and 326 to skin, then attaches theacoustic port 302 to the adhesive 326, and then connects the support 301to the upper side of the adhesive 325 (being a double sided adhesive).Finally, the connector 320 is connected to the cables and fibers fromthe control unit to allow the operation of the probe. Each element ofthe flexible probe 403 and the complete probe 403 as a unit may be usedonly once and then discarded (i.e., is disposable), or used multipletimes.

FIGS. 8A and 8B show, respectively, bottom and side views of a probe 403in which a support 301 carries light ports (or light sources) andseveral acoustic ports 302, 319 and 319A (or acoustic transducerarrangements). Each of the acoustic ports 302, 319 and 319A is coupledto a connector 320 using cables 338, 339 and 339A, respectively.Adhesive gels 326, 329 and 329A are used to couple the acoustic ports302, 319 and 319A, respectively, to the skin. Similarly, each of theacoustic ports may be separated from the probe 403 when not in use, andinserted by user for as preparation for operation.

Those skilled in the art will readily appreciate that variousmodifications and changes may be applied to the embodiments of theinvention as hereinbefore described without departing from its scopedefined in and by the appended claims.

1. (canceled)
 2. Apparatus comprising a measurement system forperforming non-invasive measurements on a subject's body, the systemcomprising: a measurement unit comprising: an acoustic unit configuredto direct acoustic radiation toward a region of interest within thesubject's body; and an optical unit comprising: an illumination assemblythat comprises at least one light emitter, and at least one first and atleast one second light guiding unit, the light emitter and the first andsecond light guiding units being optically coupled to each other via afirst optical coupler; and a light detection assembly that comprises atleast one light detector, the at least one second light guiding unit,and at least one third light guiding unit, the light detector, thesecond light guiding unit, and the third light guiding unit beingoptically coupled to each other via a second optical coupler, themeasurement unit being configured to provide a first operating conditionsuch that: the acoustic unit directs acoustic radiation toward a regionof interest within the subject's body, a first light portion istransmitted from the light emitter to the light detector, by beingtransmitted along the second light guiding unit, from the first opticalcoupler to the second optical coupler, without passing through tissue ofthe subject, and a second light portion is transmitted from the lightemitter to the light detector, by being transmitted from the first lightguiding unit to the third light guiding unit via the region of interestwithin the subject's body, such that scattered light of the first lightportion that passes into the third light guiding unit contains a taggedcomponent corresponding to photons tagged by the acoustic radiation, andan untagged component corresponding to photons untagged by the acousticradiation, and a control unit configured to determine a property oftissue of the region of interest, by decoupling from each other thetagged and untagged components of the second light portion received atthe light detector, based upon an interaction between light of the firstlight portion and light of the second light portion received at thelight detector.
 3. The apparatus according to claim 2, wherein thefirst, second, and third light guiding units comprise, respectively,first, second and third optical fibers.
 4. The apparatus according toclaim 2, wherein the first, second, and third light guiding unitscomprise, respectively, first, second, and third optical fiber bundles.5. The apparatus according to claim 2, wherein the measurement unit isconfigured to provide the first operating condition, by providing anoperating condition such that light of the first light portion iscoherent with light of the second light portion.
 6. The apparatusaccording to claim 2, wherein: the measurement unit is configured tofurther provide a second operating condition such that the secondoptical coupler blocks the second light portion from arriving at thelight detector by blocking light that is transmitted via the thirdoptical guiding unit, and the control unit is configured to determine aparameter of light emitted by the light emitter, by analyzing light ofthe first light portion that was received at the light detector, whilethe measurement unit provided the second operating condition.
 7. Theapparatus according to claim 2, wherein: the measurement unit isconfigured to further provide a second operating condition such that:the acoustic unit does not direct acoustic radiation toward the regionof interest within the subject's body, the first light portion istransmitted from the light emitter to the light detector by beingtransmitted along the second light guiding unit from the first opticalcoupler to the second optical coupler without passing through tissue ofthe subject, and the second light portion is transmitted from the lightemitter to the light detector by being transmitted from the first lightguiding unit to the third light guiding unit via the region of interestwithin the subject's body, such that scattered light of the first lightportion that passes into the third light guiding unit contains photonsuntagged by the acoustic radiation, and does not contain photons thatwere tagged by the acoustic radiation, and the control unit isconfigured to determine the property of the tissue of the region ofinterest, by comparing light received at the light detector while themeasurement unit was operating at the first operating condition to lightreceived at the detector while the measurement unit was operating at thesecond operating condition.
 8. The apparatus according to claim 2,wherein: the measurement unit is configured to provide a secondoperating condition such that the second optical coupler is configuredto block the first light portion from arriving at the light detector byblocking light that is transmitted via the second optical guiding unit,and the control unit is configured to: analyze light that was receivedat the light detector, while the light of the first light portion wasblocked from arriving at the light detector, and in response thereto,decouple a contribution of the first light portion from an interferencepattern that was detected at the light detector, while the measurementunit was providing the first operating condition.
 9. The apparatusaccording to claim 2, further comprising a light modulator configured tobe disposed along an optical path along the second light guiding portionand to shift a frequency of light of the first light portion that passesthrough the light modulator, such that photons of the first lightportion that are received at the light detector are frequency modulatedwith respect to a frequency of the photons when the photons were emittedfrom the light emitter.
 10. The apparatus according to claim 9, whereinthe second light guiding unit comprises at least one first optical fiberconfigured to guide light from the first optical coupler to an entryface of the light modulator, and at least one second optical fiberconfigured to guide light from an exit face of the light modulator tothe second optical coupler.
 11. The apparatus according to claim 9,wherein the light modulator is configured to shift the frequency ofphotons of the first light portion by a first frequency shift, andwherein the acoustic radiation is configured to shift a frequency of thetagged photons of the second light portion by a second frequency shift,the first and second frequency shifts being different from one another.12. The apparatus according to claim 9, wherein: by operating at thefirst operating condition, the measurement unit is configured togenerate an interference pattern at the light detector based upon aninteraction of the tagged photons of the second light portion, theuntagged photons of the second light portion, and thefrequency-modulated photons of the first light portion, and wherein thecontrol unit is configured to determine the property of the tissue ofthe region of interest by analyzing relative amplitudes of respectivecomponents of the interference pattern.
 13. The apparatus according toclaim 9, wherein the measurement unit is configured to operate at thefirst measurement condition by controlling a ratio between a number ofphotons in the first light portion and a number of tagged photons in thesecond light portion.
 14. A method for performing non-invasivemeasurements on a subject's body, the method comprising: directingacoustic radiation toward a region of interest within the subject'sbody; transmitting light from a light emitter to a light detector undera first operating condition, such that: a first light portion istransmitted from the light emitter to the light detector without passingthrough tissue of the subject, a second light portion is transmittedfrom the light emitter to the light detector via the region of interestwithin the subject's body, such that scattered light of the second lightportion that is received at the light detector contains a taggedcomponent corresponding to photons tagged by the acoustic radiation, andan untagged component corresponding to photons untagged by the acousticradiation, transmitted light of the first light portion is opticallycoupled to transmitted light of the second light portion, and light ofthe first light portion undergoes an interaction with received light ofthe second light portion at the light detector, by received light of thefirst and second light portions being optically coupled to each other;detecting the light received at the light detector; and determining aproperty of tissue of the region of interest, by decoupling from eachother the tagged and untagged components of the second light portionreceived at the light detector, based upon the interaction between thereceived light of the first portion and the received light of the secondlight portion.
 15. The method according to claim 14, whereintransmitting light from the light emitter to the light detectorcomprises transmitting light through optical fibers.
 16. The methodaccording to claim 14, wherein transmitting light from the light emitterto the light detector comprises transmitting light through optical fiberbundles.
 17. The method according to claim 14, wherein transmittinglight from the light emitter to the light detector comprisestransmitting light from the light emitter to the light detector suchthat light of the first light portion is coherent with light of thesecond light portion.
 18. The method according to claim 14, furthercomprising: transmitting light from the light emitter to the lightdetector under a second operating condition, by blocking the secondlight portion from arriving at the light detector, and determining aparameter of light emitted by the light emitter, by analyzing light ofthe first light portion that was received at the light detector, whilethe second light portion was blocked.
 19. The method according to claim14, further comprising transmitting light from the light emitter to thelight detector under a second operating condition, while the acousticradiation is not being directed toward the region of interest, suchthat: the first light portion transmitted from the light emitter to thelight detector without passing through tissue of the subject, and thesecond light portion is transmitted from the light emitter to the lightdetector via the region of interest within the subject's body, such thatscattered light of the first light portion that is received at the lightdetector contains photons untagged by the acoustic radiation, and doesnot contain photons that were tagged by the acoustic radiation, whereindetermining the property of tissue of the region of interest comprisescomparing light received at the light detector while light wastransmitted from the light emitter to the light detector at the firstoperating condition, to light received at the detector while light wastransmitted from the light emitter to the light detector at the secondoperating condition.
 20. The method according to claim 14, furthercomprising: transmitting light from the light emitter to the lightdetector under a second operating condition, by blocking the first lightportion from arriving at the light detector, analyzing light that wasreceived at the light detector, while the second light portion wasblocked from arriving at the light detector, and in response thereto,decoupling a contribution of the first light portion from aninterference pattern that was detected at the light detector due to theinteraction of the first and second light portions, while the light wastransmitted from the light emitter to the light detector under the firstoperating condition.
 21. The method according to claim 14, furthercomprising shifting a frequency of light of the first light portion,such that photons of the first light portion that are received at thelight detector are frequency modulated with respect to a frequency ofthe photons when the photons were emitted from the light emitter. 22.The method according to claim 21, wherein: shifting the frequency oflight of the first light portion comprises shifting the frequency ofphotons of the first light portion by a first frequency shift, anddirecting the acoustic radiation toward the region of interest comprisesshifting a frequency of the tagged photons of the second light portionby a second frequency shift, the first and second frequency shifts beingdifferent from one another.
 23. The method according to claim 21,wherein transmitting light from the light emitter to the light detectorunder the first operating condition comprises generating an interferencepattern at the light detector based upon an interaction of the taggedphotons of the second light portion, the untagged photons of the secondlight portion, and the frequency-modulated photons of the first lightportion, and wherein determining the property of tissue of the region ofinterest comprises analyzing relative amplitudes of respectivecomponents of the interference pattern.
 24. The method according toclaim 21, wherein transmitting light from the light emitter to the lightdetector under the first operating condition, comprises controlling aratio between a number of photons in the first light portion and anumber of tagged photons in the second light portion.